U.S. patent application number 17/537922 was filed with the patent office on 2022-08-18 for autoinjector with stall and end point detection.
The applicant listed for this patent is AMGEN INC.. Invention is credited to Nicola Antonio Alagia, Antonio Antonini, Andrew Coles, Sivakumar Paramanandam.
Application Number | 20220257864 17/537922 |
Document ID | / |
Family ID | 1000006305667 |
Filed Date | 2022-08-18 |
United States Patent
Application |
20220257864 |
Kind Code |
A1 |
Paramanandam; Sivakumar ; et
al. |
August 18, 2022 |
AUTOINJECTOR WITH STALL AND END POINT DETECTION
Abstract
An autoinjector drug delivery device configured with a stall and
endpoint detection algorithm is described that allows for
variations in the fill of the drug, barrel, plunger, and other
components. The stall or end point detection can cause the
autoinjector to stop an extrusion process.
Inventors: |
Paramanandam; Sivakumar;
(Newbury Park, CA) ; Coles; Andrew; (Thousand
Oaks, CA) ; Alagia; Nicola Antonio; (Milano, IT)
; Antonini; Antonio; (Milano, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Family ID: |
1000006305667 |
Appl. No.: |
17/537922 |
Filed: |
November 30, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16188496 |
Nov 13, 2018 |
11213626 |
|
|
17537922 |
|
|
|
|
62587421 |
Nov 16, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/31545 20130101;
A61M 2005/2006 20130101; A61M 5/145 20130101; A61M 5/3135 20130101;
A61M 5/20 20130101; A61M 5/3157 20130101; A61M 5/322 20130101; A61M
5/24 20130101 |
International
Class: |
A61M 5/24 20060101
A61M005/24; A61M 5/31 20060101 A61M005/31; A61M 5/315 20060101
A61M005/315; A61M 5/145 20060101 A61M005/145; A61M 5/20 20060101
A61M005/20 |
Claims
1. A drug delivery device comprising: a reservoir configured to
contain a drug and having a first end and a second end; a plunger
disposed within the reservoir at the first end thereof, the plunger
slidingly movable within the reservoir; a plunger rod configured to
engage the plunger; a motor operably coupled to the plunger rod and
configured to drive the plunger rod to thereby slide the plunger
from the first end of the reservoir to the second end of the
reservoir; an encoder operably coupled to the motor; and a
controller configured for (i) receiving signals from the encoder,
(ii) determining a position and/or movement of the plunger within
the reservoir based on the signals, and (iii) determining whether
to stop operation of the motor based on the position and/or
movement of the plunger.
2. The drug delivery device of claim 1, wherein the encoder
includes a disk having one or more discernible portions and an
optical sensor configured to detect the discernible portions and
send a signal in response to the detection.
3. The drug delivery device of claim 1, wherein a count of the
signals is indicative of a position of the plunger rod and the
controller is configured for sampling the position of the plunger
rod at set intervals by determining a current count of the
signals.
4. The drug delivery device of claim 3, wherein the controller
determining whether to stop operation of the motor based on the
position and/or movement of the plunger comprises comprises the
controller determining whether the signals indicate that the
plunger has moved within a predetermined number of samples of the
signals.
5. The drug delivery device of claim 4, wherein the controller is
configured to compare the current count to an expected endpoint
count corresponding to the plunger being driven to the second end
of the reservoir.
6. The drug delivery device of claim 5, wherein the controller is
configured to revise the predetermined number of samples in
response to determining that the current count is less than the
expected endpoint.
7. The drug delivery device of claim 5, wherein the controller is
configured to determine that the plunger has stalled in response to
determining that the current count is less than the expected
endpoint.
8. The drug delivery device of claim 1, further comprising a needle
and a needle insertion mechanism, and wherein the controller is
configured for causing the needle insertion mechanism to retract
the needle in response to determining to stop operation of the
motor.
9. The drug delivery device of claim 1, wherein the drug delivery
device comprises an autoinjector.
10. A method for operating a drug delivery device, the method
comprising: receiving signals at a controller from an encoder
coupled to a motor of the drug delivery device, the motor operably
coupled to a plunger rod configured to engage and drive a plunger
within a reservoir; determining a position and/or movement of the
plunger within the reservoir based on the signals, and determining
whether to stop operation of the motor based on the position and/or
movement of the plunger.
11. The method of claim 10, further comprising: detecting a
discernible portion of a disk of the encoder with an optical
sensor; and sending a signal in response to the detection.
12. The method of claim 10, further comprising sampling a position
of the plunger rod at set intervals with the controller by
determining a current count of the signals.
13. The method of claim 12, wherein determining whether to stop
operation of the motor based on the position and/or movement of the
plunger comprises determining whether the signals indicate that the
plunger has moved within a predetermined number of samples of the
signals.
14. The method of claim 13, further comprising comparing the
current count to an expected endpoint count corresponding to the
plunger being driven to a second end of the reservoir.
15. The method of claim 14, further comprising revising the
predetermined number of samples in response to determining that the
current count is less than the expected endpoint.
16. The method of claim 14, further comprising determining that the
plunger has stalled before being driven to the second end of the
reservoir in response to determining that the current count is less
than the expected endpoint.
17. The method of claim 10, further comprising retracting a needle
of the drug delivery device with a needle insertion mechanism in
response to the controller determining to stop operation of the
motor.
18. The method of claim 10, wherein the drug delivery device
comprises an autoinjector.
19. The drug delivery device of claim 1, further comprising a drug
in the reservoir, wherein the drug comprises etanercept.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This is a continuation of U.S. patent application Ser. No.
16/188,496, filed Nov. 13, 2018, which claims the priority benefit
of U.S. Provisional Patent Application No. 62/587,421, filed Nov.
16, 2017, the entire contents of each of which being hereby
expressly incorporated herein by reference.
FIELD OF THE DISCLOSURE
[0002] The disclosure relates to injection systems and apparatus.
More particularly, the disclosure relates to operation of an
autoinjector apparatus.
BACKGROUND
[0003] Pre-filled hypodermic syringes can be used for home-use
because they may be prepared with a required dosage of a
pharmaceutical product and are operated by merely advancing the
stopper of the syringe. Aside from the costs of the particular
medication used, pre-filled syringes may be economically
manufactured.
[0004] Nevertheless, pre-filled syringes can have drawbacks.
Specifically, many users are either frightened by an exposed
injection needle or feel they are inherently incapable of
performing an injection. Because of aversions to exposed needles,
as well as health and safety issues that may be involved, various
types of injectors and other devices have been developed for
concealing needles from the user and automating the injection task
to assist the user in performing the injection, ensure reliable
delivery of the medication and ensure patient safety. See the
following patents or patent applications, which are each herein
incorporated by reference in its entirety: U.S. Pat. Nos. 8,052,645
and 8,177,749; U.S. Publ. No. 2012/0101439; and PCT Publ. No. WO
2012/145685.
[0005] Typically, three tasks may be performed when injecting a
drug into a patient with a hypodermic syringe: 1) insertion of the
needle into the patient; 2) injection of the drug from the syringe
into the patient; and 3) withdrawal of the needle after the
injection has been completed. For each task, the magnitude and
direction of forces on the syringe, as well as the location of
their application, may be different from the other tasks. For
example, insertion of the needle may require the application of a
minimal force on the syringe, for a very short period of time. On
the other hand, injection of the medicament may require the
application of a much greater force on the plunger of the syringe,
and this force may need to be applied for a relatively longer
period of time. Further, needle withdrawal may require the
application of a force in an opposite direction from needle
insertion. These, and other similar considerations, may become
relevant when the injection process is to be automated.
[0006] In addition to these mechanical considerations, the design
of an autoinjector may require user-friendly considerations. In
particular, it may be desirable for the injection needle of the
syringe to be operationally concealed from the view of a user.
Preferably, this concealment is maintained before, during and after
an injection procedure. Further, it may be desirable that operation
of the syringe be limited to only those times when the syringe is
properly positioned for an injection and/or when the appropriate
sequence of actions are performed by the user.
[0007] When subcutaneously injecting a drug, patients may desire a
swift, but smooth and steady injection. The length that the needle
is disposed within the patient is balanced against the feel of the
drug flow entering into the subcutaneous space. In one form, drug
delivery devices can determine that a dose of drug has been
dispensed by moving a plunger rod to a fixed, end position from a
starting position. Moving to such a fixed position, however, can
leave some drug within the syringe if too conservative or can break
the glass of the syringe if too aggressive. Further, if the plunger
stalls in the middle of an extrusion before the plunger rod reaches
the end position, the plunger rod can embed in or bypass the
plunger in an attempt to get to the end position. Additionally, in
closed loop feedback systems, stall detection is more difficult
where consistent injection speed is the aim.
[0008] A plunger can stall due to any number of circumstances. For
example, manufacturing variations in anything from fill volume,
plunger installation location, plunger composition or temperature
for compression thereof, siliconization of the plunger or syringe,
syringe tapering or shape, motor capability, battery performance
effecting injection speed, and so forth can cause variations in
extrusion speeds over the injection process. Additionally,
conditions can effect extrusion speeds, such as temperature of the
drug affecting the viscosity thereof, local heating in the windings
of the motor causing engine performance degradation.
SUMMARY
[0009] A drug delivery device is described herein that includes a
reservoir configured to contain a drug and that has a first end and
a second end, a plunger disposed within the reservoir at the first
end thereof, where the plunger is slidingly movable within the
reservoir. The device further includes a plunger rod configured to
engage the plunger, a motor operably coupled to the plunger rod and
configured to drive the plunger rod to thereby slide the plunger
from the first end of the reservoir to the second end of the
reservoir, and an encoder coupled to the motor. The device further
includes a controller that is configured to receive signals from
the encoder, determine whether the plunger has stopped moving
within the reservoir based on the signals, and stop operation of
the motor in response to determining that the plunger has stopped
moving for a predetermined amount of time.
[0010] In various embodiments, the encoder can include a disc
having one or more discernible portions and an optical sensor
configured to detect the discernible portions and send a signal in
response to the detection.
[0011] In various embodiments, the drug delivery device can further
include a needle and a needle insertion mechanism, and the
controller can be configured to retract the needle in response to
determining that the plunger has stopped moving for the
predetermined amount of time.
[0012] A method is described herein for operating a drug delivery
device. The method includes receiving signals at a controller from
an encoder coupled to a motor of the drug delivery device, the
motor operably coupled to a plunger rod configured to engage and
drive a plunger within a reservoir, determining whether the plunger
has stopped moving within the reservoir with the controller based
on the signals, and stopping operation of the motor with the
controller in response to determining that the plunger has stopped
moving for a predetermined amount of time.
[0013] In various embodiments, the method can further include
detecting a discernible portion of a disk of the encoder with an
optical sensor, and sending a signal in response to the
detection.
[0014] In various embodiments, the method can further include
sampling the position of the plunger rod at set intervals with the
controller by determining a current count of the signals.
[0015] In various embodiments, determining whether the plunger has
stopped moving within the reservoir can include determining whether
the signals indicate that the plunger has moved within the last
predetermined number of samples. In further embodiments, the method
can further include comparing the current count to an expected
endpoint count corresponding to the plunger being driven to the
second end of the reservoir. In yet further embodiments, the method
can include revising the predetermined number of samples in
response to determining that the current count is less than the
expected endpoint. In further embodiments, the method can include
determining that the plunger has stalled before being driven to the
second end of the reservoir in response to determining that the
current count is less than the expected endpoint.
[0016] In various embodiments, the method can further include
retracting a needle of the drug delivery device with a needle
insertion mechanism in response to the controller determining that
the plunger has stopped moving for the predetermined amount of
time.
[0017] It should be noted that while the specification frequently
refers to an autoinjector, in various embodiments the device may
also be referred to as an injector. Reference to an autoinjector is
often associated with a patient providing an injection to themself,
however, such an injection may also be administered by a health
care provider. Similarly, use of an injector may be undertaken by
either the patient or health care provider.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The accompanying figures show embodiments according to the
disclosure and are exemplary rather than limiting.
[0019] FIG. 1 is a side view of an embodiment of an autoinjector
apparatus comprising a cassette and an autoinjector, showing the
cassette prior to installation in the autoinjector.
[0020] FIG. 2A is a front view of the autoinjector apparatus of
FIG. 1 showing the cassette installed in the autoinjector.
[0021] FIG. 2B is a side view of a first side of the autoinjector
apparatus of FIG. 1 showing the cassette installed in the
autoinjector.
[0022] FIG. 2C is a rear view of the autoinjector apparatus of FIG.
1 showing the cassette installed in the autoinjector.
[0023] FIG. 2D is side view of a second side of the autoinjector
apparatus of FIG. 1 showing the cassette installed in the
autoinjector.
[0024] FIG. 2E is an end view of a first end of the autoinjector of
the autoinjector apparatus of FIG. 1.
[0025] FIG. 2F is an end view of a second end of the autoinjector
of the autoinjector apparatus of FIG. 1.
[0026] FIG. 2G is a state diagram showing an embodiment of the
decision logic for controlling a skin sensor of the autoinjector
apparatus of FIG. 1.
[0027] FIG. 2H is a sectional side view of an embodiment of the
autoinjector apparatus showing the cassette installed in the
autoinjector.
[0028] FIG. 2I is a diagrammatic view of a motor and encoder for
determining plunger travel distance for the autoinjector apparatus
of FIG. 1.
[0029] FIG. 3 is an exploded perspective view of an embodiment of
the cassette.
[0030] FIG. 4 is a sectional side view of an embodiment of a drug
container that can be provided in the cassette.
[0031] FIG. 5A is a top down front perspective view of an
embodiment of the cassette.
[0032] FIG. 5B is a sectional side view of the cassette of FIG.
5A.
[0033] FIG. 5C is a sectional side view of the cassette of FIG. 5A
after removal of a cassette cap of the cassette.
[0034] FIG. 5D is a sectional side view of the cassette of FIG. 5C
showing a prefilled drug container of the cassette in a
needle-injected position.
[0035] FIG. 6A is a bottom down front perspective view of an
embodiment of the cassette showing an inner sleeve latch mechanism
and an inner sleeve locking arrangement.
[0036] FIG. 6B is a bottom view of an embodiment of an outer
housing of the cassette shown in FIG. 6A showing certain elements
of the inner sleeve latch mechanism and the inner sleeve locking
arrangement.
[0037] FIGS. 7A and 7B are top down and bottom down front
perspective views, respectively, of an embodiment of the cassette
with a cassette identification arrangement.
[0038] FIG. 8A is a bottom down perspective view of a portion of
the cassette showing an embodiment of the cassette identification
arrangement.
[0039] FIG. 8B is a sectional side view of the cassette of FIG. 8A
being inserted into an autoinjector constructed to detect and
decipher the cassette identification arrangement embodied in FIG.
8A.
[0040] FIG. 9A is a bottom down perspective view of a portion of
the cassette showing another embodiment of the cassette
identification arrangement.
[0041] FIG. 9B is a sectional side view of the cassette of FIG. 9A
being inserted into an autoinjector constructed to detect and
decipher the cassette identification arrangement embodied in FIG.
9A.
[0042] FIG. 10A is a bottom down front perspective view of a
portion of the cassette showing another embodiment of the cassette
identification arrangement.
[0043] FIG. 10B is a sectional side view of the cassette of FIG.
10A being inserted into an autoinjector constructed to detect and
decipher the cassette identification arrangement embodied in FIG.
10A.
[0044] FIG. 11A is a bottom down perspective view of a portion of
the cassette showing a further embodiment of the cassette
identification arrangement.
[0045] FIG. 11B is a bottom down perspective view of a portion of
the cassette showing still another embodiment of the cassette
identification arrangement.
[0046] FIG. 11C is a bottom down perspective view of a portion of
the cassette showing yet another embodiment of the cassette
identification arrangement.
[0047] FIG. 11D is a bottom down perspective view of a portion of
the cassette showing another embodiment of the cassette
identification arrangement.
[0048] FIG. 12 is a flow chart showing an embodiment of a method
for assembling different product lines on a single manufacturing
line using the cassette identification arrangement to control the
assembly of prefilled drug containers (containing a range of
different drugs and/or fill levels) and to rout the assembled
cassettes to the appropriate packaging stations.
[0049] FIG. 13 is a bottom up perspective view of the autoinjector
of the autoinjector apparatus or system showing the installation of
a cassette into the autoinjector.
[0050] FIG. 14 is a flow chart showing an embodiment of the
decision logic for forcing a user to execute the steps of an
injection process in a safe and reliable order.
[0051] FIG. 15 is a flow chart showing an end point and stall
detection algorithm.
[0052] FIG. 16 is a graph showing an extrusion process for an
autoinjector device.
DETAILED DESCRIPTION
[0053] FIG. 1 shows an embodiment of an autoinjector system or
apparatus 100 that can be used for injecting a dose of
pharmaceutical product (drug) into a patient, the injection often
being self-administered by the patient (user). Alternatively, the
drug can be administered by a health-care provider. As shown, the
autoinjection system or apparatus 100 may comprise a removable
cassette 200 and an autoinjector or injector 300. Various
embodiments of the cassette 200 may be constructed to contain a
drug to be injected into the user by the autoinjector 300. In
various other embodiments the cassette 200 may be constructed for
use in training the user to operate the autoinjector 300 (a
training cassette). The autoinjector 300 may be constructed to
deliver an injection automatically upon actuation by the user or
some other person. Various embodiments of the autoinjector 300 may
have a cassette door 308 that can be constructed to pivot between
and an open position and a closed position to allow insertion of
the cassette 200 into the autoinjector 300. In some embodiments,
the cassette door 308 may include a "cassette" icon (not shown)
that indicates the insertion entry point for the cassette 200.
[0054] Referring collectively to FIGS. 2A-2F, various embodiments
of the autoinjector 300 may comprise a casing 302 having a handle
section 304 and a cassette receiving section 306 inline with the
handle section 304. To aid patients with manual dexterity issues,
the handle section 304 of the autoinjector casing 302 may define an
ergonomically shaped handle 305 with a soft grip area 305S. The
cassette receiving section 306 comprises the cassette door 308
(FIGS. 2B and 2D) described earlier. The cassette door receives the
cassette 200 in an open position (FIG. 1) and aligns the cassette
200 with insertion and extrusion drives, and other structures and
components of the autoinjector 300 in a closed position. The
cassette door 308 may include a "cassette" icon that indicates the
insertion entry point for the cassette 200. The cassette receiving
section 306 of the casing 302 may comprise windows 310A, 310B on
sides thereof that align with windows of the cassette 200 when the
cassette door 308 is closed with the cassette 200 correctly
installed therein. In one or more embodiments, the windows 310A,
310B may be double-layered. One or more lights (not shown) may be
provided inside the casing 302 to evenly backlight illuminate the
cassette windows 212 (FIG. 5A) and the syringe 260 disposed within
the inner sleeve 220 of the cassette 200 (FIG. 5B), so that the
user can observe the injection cycle through the windows 310A, 310B
of the autoinjector 300, i.e., observe the initial and end
positions of the plunger-stopper 264 of the syringe 260 (FIG. 5B)
during the syringe content (hereinafter "drug") extrusion process,
as well as syringe movements within the cassette 200.
[0055] Referring still to FIGS. 2A, 2B, 2D, and 2F, the
autoinjector 300 may further comprise a user interface 312 and an
audio speaker (not shown). The user interface 312 (best illustrated
in FIG. 2A) may be located in the cassette receiving section 306 of
the casing 302, and provides various visual indicators. The audio
speaker may be disposed inside the casing 302 and provides various
audible indicators. The audio speaker may audibly communicate with
the external environment via a speaker aperture 314 formed in the
casing 302 in the cassette receiving section 306. The visual and
audible indicators generated by the user interface 312 and the
audio speaker can tell the user when the autoinjector 300 is ready
for use, the progress of the injection process, injection
completion, the occurrence of any errors, and other information.
The autoinjector 300 may further comprise one or more of a
settings/mute switch 315, a speed selector switch 316, a start
button 307, and an eject button 317. The settings/mute switch 315
(FIG. 2B) may be located in the cassette receiving section 306 of
the casing 302. The mute switch 315 may be constructed allow the
user to turn on and off all synthesized sounds, except error
sounds, and to respond in real-time so that if the user begins the
injection process and changes the mute switch to off, the sounds
are immediately muted. The mute switch 315 may also be constructed
to slide toward a "mute" icon to mute the audio speaker. A light
indicator may be provided to confirm the "mute" state. The speed
selector switch 316 (FIGS. 2A and 2B) may be located in the
cassette receiving section 306 of the casing 302. The speed
selector switch 316 may be constructed to allow the user to select
among a plurality of preset drug delivery (extrusion) speeds to
accommodate personal patient preference. The speed selector switch
316 may comprise a three switch positions. Other embodiments of the
speed selector switch may comprise two switch positions, or 4 or
more switch positions. In still other embodiments, the speed
selector switch may be of the infinitely variable type. In some
embodiments, changing the position of the switch 316 prior to
injection changes the speed of drug extrusion during injection
while changing the position of the speed selector switch 316 during
injection, does not change the speed of the injection in real time.
The autoinjector 300 may also be provided with one or more demo
cassettes to allow the user to experiment with different speeds of
drug delivery. The start button 307 may be disposed at a free end
of the handle 305. The button 307 may include an indentation 307i
(FIG. 2F) for optimizing thumb placement on the button 307. The
button 307 may be made of a translucent material that allows a
lighting effect to illuminate the button as signals. The eject
button 317 (FIG. 2D) may be located in the cassette receiving
section 306 of the casing 302. The eject button 317 may include an
indentation 317i for optimizing finger placement on the button 317.
In some embodiments, the eject button 317 may be controlled by a
microprocessor 350 (FIG. 2H) of the autoinjector 300, which may be
programmed to eliminate accidental inputs during the injection
process.
[0056] Referring to FIG. 2E, the cassette receiving section 306 of
the casing 302 and the cassette door 308 may form a proximal end
wall 318 of the autoinjector 300. The proximal end wall 318 may be
configured as a broad, flat and stable base for easily positioning
the autoinjector 300 on a support surface, after removal of the
shield remover 240 (FIG. 5A) or when the autoinjector 300 does not
contain the cassette 240. The portion of the proximal end wall 318
formed by the cassette door 308 may include an aperture 308A that
is sized and shaped to allow the shield remover 240 to be removed
from the cassette 200 and withdrawn through the aperture 308A, when
the cassette 200 is installed in the autoinjector 300. The proximal
end wall of the autoinjector 300 may further comprise a target
light 320. The target light 320 may be constructed to turn on when
the shield remover 240 is removed from the cassette 200 and
withdrawn through the aperture 308A, thereby visually indicating
that the shield remover 240 has been removed. Once turned on, the
target light aids the user in visualizing and selecting an
injection site.
[0057] Referring still to FIG. 2E, the autoinjector 300 may further
comprise a capacitance-based skin sensor 380 (shown with broken
lines) or any other suitable skin sensor. The skin sensor 380 may
coupled to a microprocessor provided, for example, in the
autoinjector 300 in a manner that allows signals or data to be
communicated to the microprocessor, so that the autoinjector 300
can determine when the proximal end wall 318 of the autoinjector
300 touches or contacts skin without the need to provide downward
pressure on the injection-site area. The skin sensor 380 may also
be constructed to inform the user through audible and visual
indicators generated by the speaker and user interface, when skin
contact is detected. In some embodiments, the skin sensor 380 may
comprise two pads or electrodes (not shown) located adjacent to an
inner surface of or embedded in the proximal end wall 318 of the
autoinjector 300. When the proximal end wall 318 is placed in
contact with the skin, the electrode's capacitance signal
increases. If the increase is sufficient as determined by the
microprocessor, which may be programmed with sensor decision logic,
that electrode will become activated. To determine whether skin
contact has been made, the microprocessor reads the capacitance of
the electrodes. The microprocessor then processes the capacitance
information from both electrodes to determine when the proximal
wall 318 makes proper contact with the skin. In the embodiment
where the electrodes are disposed on the inner surface of the
proximal wall 318, the electrodes themselves never make contact
with skin, only the plastic housing makes contact with skin, with
the electrodes attached to the housing on the inside. Such a design
would account for the distance of the electrodes from the skin
(spaced by the proximal wall 318) as well as the housing material
response in how the calculation determines that the device is in
contact with (or in actuality just very close to) the injection
site.
[0058] FIG. 2G is a state diagram illustrating the decision logic
for controlling skin sensor 380 with the microprocessor of the
autoinjector 300, according to an embodiment of the present
disclosure. The process starts at 400 which represents a reset of
the autoinjector. The logic then flows to state 402 which
represents the initialization of the skin sensor after the reset of
the autoinjector. Once initialized, the logic flows to state 404
which represents a "no-touch" state where none or only one of the
electrodes of the sensor sense that the proximal end wall 318
touches the skin. If both electrodes sense that the proximal end
wall 318 touches skin for less than a certain threshold time period
(e.g., one second), the logic flows to state 406 which represents a
"touching" state. If one or neither one of the electrodes sense
that the proximal end wall 318 touches skin, the logic flows back
to state 404. If, however, both electrodes sense that the proximal
end wall 318 touches skin for a period of time equal to the
threshold time period (e.g., one second), the logic flows to state
408 which represents a "touch OK" state. If one electrode or no
electrodes sense that the proximal end wall 318 contacts skin, the
logic flows to a "releasing" state 409. If both electrodes touch
skin, the logic flows back to "touch OK" state 408. If one or no
electrodes contact skin for more than the threshold time period
(e.g., more than one second), the logic flows back to "no touch"
state 404.
[0059] In a further approach, the autoinjector 300 can include
multiple sensors 380 so that the microprocessor 350 can analyze the
capacitance measured by each sensor 380. Correct positioning of the
autoinjector 300 can be determined, in this embodiment, by a
predetermined level of capacitance in each sensor 380 for a
predetermined amount of time. Further, based on continually reading
or periodically sampling the capacitance levels of each sensor 380,
the microprocessor 350 can determine if one or more sensors 380 are
losing capacitance, which could indicate that the user is tilting
the injector 300. Thereafter, if a sensor 380 drops below a
threshold for a predetermined amount of time, the microprocessor
350 can follow the above logic to reorient the injector 300. This
embodiment can help a user operate the autoinjector 300 with
reduced errors due to nervousness, tremors, or fidgeting.
[0060] As shown in FIG. 2H, various embodiments of the autoinjector
300 may comprise a chassis 301 disposed in the casing 302 for
supporting a motorized needle insertion drive 330, a motorized drug
extrusion drive 340, a microprocessor 350, a battery 360 for
powering the drives 330, 340 and the microprocessor 350, and the
skin sensor 380. The casing 302 may define an ergonomically shaped
handle section 304 and a cassette receiving section 306. The
chassis 301 may include a support surface 301s for supporting one
or more cassettes 200 in the autoinjector 300 and aligning the
cassette 200 or a selected one of the one or more cassettes 200
with motorized needle insertion and drug extrusion drives 330 and
340, respectively. A detector 370 may be provided on or in the
cassette support surface 301s for sensing the presence of and/or
information about the cassette 200. The detector 370 may be coupled
with the microprocessor 350 in a manner that allows signals or data
to be communicated to the microprocessor 350. The insertion drive
330 may include an insertion rack 332, an insertion drive motor 331
and an insertion drive gear train 333 for transmitting rotary
motion of the insertion drive motor 331 to drive the rack 332. The
insertion rack may include a tab arrangement including, for
example, proximal and distal tabs 332p and 332d, respectively,
which interface with the cassette 200. The extrusion drive 340 may
comprise an extrusion drive motor 341, a plunger rod 342, a lead
screw 343, and an extrusion drive gear train 344. The plunger rod
342 is driven by the extrusion drive motor 341 through the lead
screw 343 and the extrusion drive gear train 344, and may interface
with a plunger 264 of a drug container 260 contained within the
cassette 200. The autoinjector 300 can be used for executing
multiple injections.
[0061] Referring still to FIG. 2H, the term microprocessor as
utilized herein refers broadly to any controller, microcontroller,
computer, or processor-based device with processor, memory, and
programmable input/output peripherals, which is generally designed
to govern the operation of other components and devices. It is
further understood to include common accompanying accessory
devices, including memory, transceivers for communication with
other components and devices, etc. These architectural options are
well known and understood in the art and require no further
description here. The microprocessor 350 may be configured (for
example, by using corresponding programming stored in a memory as
will be well understood by those skilled in the art) to carry out
one or more of the steps, actions, and/or functions described
herein. For example, the microprocessor 350 of the autoinjector 300
may be programmed with instructions that, when executed by the
microprocessor 350, enable it to control and monitor the various
operations and functions of the autoinjector 300. For example, but
not limitation, the microprocessor 350 may be programmed with
instructions for controlling the motorized insertion and extrusion
drives 330, 340. Such instructions may control and monitor each
step of the injection cycle and process flow, thereby automating
needle insertion, drug extrusion, and needle retraction, and
controlling the sequence of actions performed by the user so that
the injection process and drug administration can be made more
reliable, accurate, and consistent. The microprocessor 350 may also
be programmed with instructions for controlling the audible and
visual feedbacks to the user. An automated power-on self-test
checks the operation of the autoinjector 300 and remaining battery
charge.
[0062] In various other embodiments, the autoinjector 300 may
include other types of needle insertion drives, drug extrusion
drives, and means for activating and sequencing the drives. The
insertion and extrusion drives, in such embodiments may be
implemented as separate and distinct mechanisms or combined into a
single mechanism. The insertion and extrusion drives of such
embodiments may be powered, without limitation, by motors,
mechanical mechanisms (e.g., elastic members such as springs), gas
pressure mechanisms, gas releasing mechanism, or any combination
thereof. Various transmission mechanisms may be used for
transmitting the power to the cassette, to cause injection of the
drug. In addition, the activating and sequencing means may comprise
various mechanical and electromechanical arrangements, which may be
combined with the microprocessor described earlier or used alone.
The autoinjector in such embodiments may be constructed to be
reusable for executing multiple injections or be designed for a
single, disposable use.
[0063] By one approach, the autoinjector 300 may include an encoder
346 coupled to the motor 341 and in communication with the
microprocessor 350. The microprocessor 350 receives signals from or
queries the encoder 346 to determine a number of rotations of the
motor 341 to thereby extrapolate a distance that the plunger rod
342 and plunger 264 have traveled during an extrusion process. The
encoder 346 can take any suitable form. In the example illustrated
in FIG. 2I, the encoder 346 includes a disk 348 having discernible
portions 349 and an optical sensor 352. The disk 348 is coupled to
the motor 341 to be rotated thereby and the optical sensor 352 is
configured to identify the discernible portions 349 as they are
rotated within a sensing area of the sensor 352. The discernible
portions 349 can be windows, slits, transparent portions,
translucent portions, and so forth. If desired, the encoder 346 can
utilize a light source 354 to illuminate the discernible portions
349 so that the sensor 352 can easily detect the discernible
portions 349.
[0064] Referring now to FIG. 3, various embodiments of the cassette
200 may comprise an outer housing 210, an inner sleeve 220, a drug
container 260 for containing a drug, a cassette cap 240, a lock cap
230, and a cover 250. Such embodiments of the cassette 200
facilitate and enable easy injection of the drug with the
autoinjector and can be constructed for a single, disposable use.
In various embodiments, the lock cap 230 and cover 250 of the
cassette 200 may be constructed to resist removal of the drug
container 260 from the cassette 200, thereby preventing needle
sticks before and after use of the cassette 200 and also preventing
the drug container 260 from being taken out of the cassette 200 or
replaced. In addition, the lock cap 230 and cover 250 protect the
drug container 260 during shipment and transportation. The cassette
cap 240, in various embodiments, may be constructed to remove a
needle shield 266 covering an injection needle associated with the
drug container 260. In various other embodiments, the cassette cap
240 may also be constructed to engage the outer housing 210 of the
cassette 200, such that the cassette cap 240 cannot be rotated or
twisted, thereby preventing the needle shield 266 from damaging the
injection needle. Various embodiments of the inner sleeve 220 may
be constructed to position the drug container 260 within the
cassette housing 210 in either a needle-concealed position or a
needle injection position during an injection cycle of the
autoinjector. In various other embodiments, the outer housing 210
and the inner sleeve 220 of the cassette 200 may include one or
more locking arrangements that protect the drug container 260 and
prevent unintended needle exposure or damage. Various other
embodiments of the cassette 200 may include a cassette
identification arrangement that interfaces with the autoinjector to
communicate the installation of the cassette 200 within the
autoinjector and/or information about the cassette 200.
[0065] As shown in FIG. 4, the drug container 260 may comprise a
conventional glass or plastic syringe comprising a barrel 261 that
defines a fluid chamber 262. The fluid chamber 262 may be filled
for treatment or be prefilled with a predetermined dose of a drug
267. The drug may have a viscosity that depends on the temperature
of the product. The syringe 260 may further comprise an injection
needle 265 removably or fixedly disposed at a proximal end of the
barrel 261, and an outwardly extending flange 263 disposed at a
distal end of the barrel 261. The injection needle 265 may
communicate with the fluid chamber 262 to allow dispensing of the
predetermined dose of the drug 267 expelled from the fluid chamber
262 of the syringe barrel 261. The syringe 260 may further comprise
a moveable plunger-stopper 264, disposed within the fluid chamber
262 of the barrel 261, for expelling the predetermined dose of the
drug 267 from the chamber 262 so that it may be dispensed through
the injection needle 265. A protective needle shield 266 made, for
example, of a non-rigid material, may be provided for covering the
injection needle 265.
[0066] In some embodiments, the drug contained in the drug
container 260 may have a viscosity of about 19 centipoise, at room
temperature (20 to 25.degree. C. [68-77.degree. F.]).
[0067] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 1
centipoise and about 320 centipoise, at room temperature.
[0068] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 5
centipoise and about 40 centipoise, at room temperature.
[0069] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 10
centipoise and about 35 centipoise, at room temperature.
[0070] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 15
centipoise and about 30 centipoise, at room temperature.
[0071] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 20
centipoise and about 25 centipoise, at room temperature.
[0072] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 16
centipoise and about 42 centipoise, at room temperature.
[0073] In some embodiments, the drug contained in the drug
container 260 may have a viscosity ranging between about 1
centipoise and about 29 centipoise, at room temperature.
[0074] Referring collectively to FIGS. 5A-5D, various embodiments
of the outer housing 210 of the cassette 200 may comprise a top
wall 210t, a bottom wall 210b, side walls 210s connecting the top
and bottom walls 210t and 210b, respectively, a front or proximal
end wall 210pe and an open rear or distal end 210de. The proximal
end wall 210pe of the outer housing 210 may include an aperture 214
(FIGS. 5C and 5D), which is constructed to removably receive the
cassette cap 240. The outer housing 210 may be constructed to
retain the inner sleeve 220 therein while allowing it to be freely
moved within the outer housing 210 in a slidable manner after
removal of the cassette cap 240 (FIG. 5C). Some embodiments of the
outer housing 210 may comprise an elongated opening or window 212
in each side wall 210s thereof (FIG. 5A). The outer housing 210 of
the cassette 200 may also include a pin 215 (FIG. 5A) or any other
suitable mechanical structure that prevents the cassette 200 from
being inserted into the cassette door in the wrong direction and/or
orientation. An "arrow" icon may be provided on the outer housing
210 (not shown) to indicate the proper direction and orientation
for inserting the cassette into the cassette door.
[0075] Referring still to FIGS. 5A-5D, various embodiments of the
inner sleeve 220 may comprise proximal and distal ends 222 and 224,
respectively. The sleeve 220 may be sized and dimensioned to
directly or indirectly hold the drug container 260 therein in a
secure manner. The proximal end 222 of the inner sleeve 220 may
define an aperture 222a which is constructed to allow the injection
needle 265 of the drug container 260 to extend therethrough (FIG.
5C). The inner sleeve 220 may further comprise a drive post 268,
which allows it to be driven by the insertion drive of the
autoinjector during the needle insertion cycle of the
autoinjector's injection cycle. As can be seen in FIGS. 5C and 5D,
the inner sleeve 220 can be driven through the outer housing 210 of
the cassette 200 by the insertion drive of the autoinjector, during
which the drug container 260 moves from a distal position in the
outer housing 210 (FIG. 5C) to a proximal position in the outer
housing 210 (FIG. 5D) and then back to the distal position. When
the inner sleeve 220 is in the distal position (needle-concealed
position), as shown in FIG. 5C, the injection needle of the drug
container 260 is contained within the outer housing 210 of the
cassette 200 and concealed from view by the user. When the inner
sleeve 220 is in the proximal position (needle-injection position),
as shown in FIG. 5D, the injection needle of the drug container 260
extends out through the aperture 214 in the proximal end wall 210pe
the outer housing 210 of the cassette 200 and the autoinjector (not
shown). The lock cap 230 closes the open distal end 224 of the
inner sleeve 220 thereby locking the drug container 260 within the
inner sleeve 220, so that the drug container 260 moves with the
inner sleeve 220 as it is driven forward or backward through the
outer housing 210 by the insertion drive of the autoinjector,
during the insertion cycle of the autoinjector 300. The cover 250
closes the open distal end 210de of the outer housing 210 and
prevents tampering with the drug container 260 by encasing the
inner sleeve 220 and the drug container 260 within the outer
housing 210 of the cassette 200, and also completes the cosmetic
appearance of the cassette 200. The inner sleeve 220 may be made
from a transparent, rigid material, such as a clear polycarbonate,
to allow viewing of the drug container 260 through the windows 212
in the side walls 210s of the outer housing 210.
[0076] Referring collectively to FIGS. 6A and 6B, various
embodiments of the outer housing 210 of the cassette 200 may
comprise a latch mechanism 280 that latches the drive post 268 of
the inner sleeve 220 to retain the sleeve 220 and, therefore, the
injection needle of the drug container, in a needle-concealed
position to protect the drug container and prevent unintentional
needle exposure to the user. As best shown in FIG. 6B, the latch
mechanism 280 may include a pair of resilient, opposing latch arms
280 a formed in a bottom wall 210b of the outer housing 210, or any
other wall of the housing 210 that allows the insertion drive to
engage the drive post 268 of the inner sleeve 220. The latch arms
280a may define locking detent slots 280b (FIG. 6B) through which
the drive post 268 of the inner sleeve 220 extends.
[0077] During assembly of the cassette 200, the inner sleeve 220
containing the drug container, may be inserted into the outer
housing 210 so that the drive post 268 of the inner sleeve 220
spreads apart and slides between the latch arms 280a of the outer
housing 210 and then enters the detents slots 280b of the latch
arms 280a, where it is latched, as shown in FIG. 6A. During the
needle-insertion cycle of the autoinjector, the insertion drive
moves the distal tab 332d in the proximal direction thereby forcing
the latch arms 280a to spread apart and unlatch the drive post 268
of the inner sleeve 220, thereby allowing proximal and distal
movement of the unlatched inner sleeve 220 through the cassette
outer housing 210, via the drive post 268.
[0078] Once unlatched, the insertion drive can move the inner
sleeve 220 and, therefore, the drug container disposed therein from
the needle-concealed position to the needle injection position. At
the completion of the autoinjector's drug-extrusion cycle, the
insertion drive moves the drive post 268 and, therefore, the inner
sleeve 220 containing the spent drug container back to the
needle-concealed position where the drive post 268 is again latched
between the latch arms 280a of the latch mechanism 280.
[0079] Various other embodiments of the cassette may further
comprise an inner sleeve locking arrangement 290, which prevents
the inner sleeve 220 from being unintentionally moved within the
outer housing 210 from the needle-concealed position. The inner
sleeve locking arrangement 290 may replace the latch mechanism 280
or provide redundancy as in the embodiment shown in FIGS.
6A-6B.
[0080] The addition of the inner sleeve locking arrangement 290
provides redundancy and increases reliability of the latch
mechanism 280, for example, to protect a user from harm, protect
the cassette contents, or prevent misuse. The inner sleeve locking
arrangement 290 provides improved resistance to motion or locking
of the inner sleeve 220 during an impact caused, for example, by a
free fall, transportation, and/or handling. Further, the inner
sleeve locking arrangement 290 improves impact energy absorption to
prevent damage to cassette components. Still further, the inner
sleeve locking arrangement 290 provides improved retention of the
inner sleeve 220 in the needle-concealed position during removal of
the needle shield to prevent exposure of the injection needle to
the environment outside the outer housing of the cassette 200. In
addition, the inner sleeve locking arrangement 290 more accurately
and repeatedly places the inner sleeve 220 in a position for
interfacing with the autoinjector.
[0081] As shown in FIG. 6B, various embodiments of the inner sleeve
locking arrangement 290 may further comprise one or more locking
feet receiving slots 294 provided in the bottom wall 210b of the
cassette outer housing 210, or any other wall of the housing that
interfaces with the cantilever lock arm 292 of the inner sleeve
220. Each of the one or more locking feet receiving slots 294 may
be provided at the ends of a pair of elongated slots 282, which
define the latch arms 280a of the latch mechanism 280. Each of the
locking feet receiving slots 294 is operative for receiving a
corresponding one of the locking feet 292f of the cantilever
locking arm 292 to effect locking of the inner sleeve locking
arrangement 290.
[0082] In the above-described embodiments, the inner sleeve locking
arrangement provides inner sleeve locking when the cantilever lock
arm is in an unbiased state. In various other embodiments, the
cantilever lock arm of the inner sleeve locking arrangement can be
constructed to provide inner sleeve locking in a biased, actuated
position. Such embodiments may be desirable, for example, to hold
the inner sleeve and thus, the drug container, in a fixed position
at a desired time. In addition, because the motor of the insertion
drives the sleeve containing the drug container, the depth of the
injection needle can be controlled. This feature can be used in
conjunction with the locking feet receiving slots and/or with
cassette identification arrangement described further on.
[0083] Referring collectively now to FIGS. 7A and 7B, various
embodiments of the cassette 200 may further comprise a cassette
identification arrangement 410, which may be constructed to
communicate information about the cassette 200 to the autoinjector.
The cassette identification arrangement 410 may be provided on an
exterior surface of the bottom wall 210bs of the cassette outer
housing 210 or any other portion of the cassette 200 that is
capable of being detected and interpreted by the autoinjector. In
some embodiments the information communicated by the cassette
identification arrangement 410 may be in the form of a code.
Specifically, the cassette identification arrangement 410 may be
constructed to generate one of a plurality of different codes, each
of which corresponds to certain characteristics of a particular
cassette 200. The code allows a suitably adapted autoinjector to
determine the type of cassette 200 inserted into the autoinjector,
i.e, whether the cassette is a training cassette (i.e., contains no
drug receptacle or contains an empty drug receptacle) or a drug
cassette containing the drug container prefilled with a drug.
Further, the code communicated by the cassette identification
arrangement 410 can tell the autoinjector what the drug contained
in the drug receptacle is and/or other cassette/drug container
characteristics. Still further, the code may provide information
that allows the autoinjector to determine, whether the cassette 200
has been inserted into the autoinjector in the proper orientation.
The autoinjector can be constructed to automatically select an
appropriate operating program and/or adjust its various operational
parameters based on the information communicated by the cassette
identification arrangement 410 (e.g., with a microprocessor as
described earlier). For example, if the autoinjector detects the
insertion of a training cassette, the autoinjector can
automatically select a training program to train the user on the
use of the autoinjector. In another example, if the autoinjector
detects the insertion of a drug cassette that contains a drug
container prefilled with a certain drug, the autoinjector can
automatically select appropriate operating parameters for injecting
that drug, such as injection speed, needle insertion speed, pre and
post-injection wait time, needle insertion depth, temperature
limits, etc. Available speed ranges may be dependent upon the drug
container fill volume and drug characteristics, such as viscosity.
Automatic selection by the autoinjector of its operating parameters
eliminates the need for the user to have to determine the
appropriate operating parameters for a given drug and then manually
input them into the autoinjector.
[0084] As shown in FIG. 8A, various embodiments of the cassette
identification arrangement 410 may comprise one or more projections
or tabs 410t provided on or in the bottom wall 210b of the cassette
outer housing 210. The number and location of the tabs 410t may
define the code or at least a portion of the code, which represents
information about the cassette 200. As shown in FIG. 8B, the
cassette identification arrangement 410 may further comprise a
detector 370 that may be provided on or in the cassette support
surface 301s of the autoinjector 300 to sense the number and
location of the tabs 410t when the cassette 200 engages the
cassette support surface 301s as the autoinjector door 308 is
closed. The detector 370 may be communicatively coupled to a
microprocessor 350 contained within the autoinjector 300, thereby
enabling the autoinjector 300 to detect the tabs 410t and obtain
the code representing the information about the cassette 200. In
various embodiments, the detector 370 may comprise a plurality of
conventional, flat-flush mounted, momentary, push-button switches
372. The switches 372 may be arranged to engage corresponding ones
of the tabs 410t. None, some, or all of the switches 372 may be
actuated by the tabs 410t of the cassette 200, depending upon the
arrangement of tabs 410t and the code they represent, when the
cassette 200 is supported on the cassette support surface 301s of
the autoinjector 300. Therefore, the code defined by the tabs 410t
and the information that the code represents about the cassette 200
can be communicated to the microprocessor 350 of the autoinjector
300 for deciphering.
[0085] The tabs 410t can be differentiated from each other by their
individual location on or in the cassette housing 210. By utilizing
the presence or absence of tabs 410t, multiple combination codes
can be created such that each code identifies a particular cassette
200 or characteristics of the cassette. Although the cassette
identification arrangement 410 shown in the embodiment of FIG. 8A
comprises three tabs 410t, various other embodiments of the
cassette identification arrangement 410 may comprise more or less
than three tabs in order to increase or decrease the number of
programming codes available. In the embodiment shown in FIG. 8A,
the presence and/or absence of one or more of the three tabs 410t
provides up to eight (8) different possible cassette identification
codes, which can be detected and deciphered by the autoinjector
300. As mentioned earlier, the information represented by each code
can be used to define one of a plurality of programming
instructions for the autoinjector 300 and/or to communicate
secondary information to the autoinjector 300, such as, but not
limited to, verifying that the cassette 200 is an authorized OEM
device, and/or verifying the proper insertion of the cassette 200
into the autoinjector 300.
[0086] Various other embodiments of the tabs 410t of the cassette
identification arrangement 410 may have different heights. In such
embodiments, the autoinjector's push-button switches 372 and
microprocessor 350 can be constructed to allow them to
differentiate between tabs 410t of the different heights, for
example, but not limitation, by how far in a button (not shown) of
the push-button switch 372 is depressed into the switch 370 by the
tab 410t. Embodiments comprising both short and tall tabs 410t can
provide each possible tab location on the cassette outer housing
210 with one of three possible states, e.g.:
[0087] State 1: no tab present
[0088] State 2: short tab present
[0089] State 3: tall tab present
[0090] If the cassette identification arrangement 410 comprises,
for example, up to three tabs 410t where each such tab 410t is
short or tall, the autoinjector could detect up to twenty-seven
(27) different tab states to increase the number of possible
codes.
[0091] As shown in FIG. 9A various other embodiments of the
cassette identification arrangement 410 may comprise one or more
indentations 410i provided in the bottom wall 210b of the outer
housing 210 of the cassette 200. As shown in FIG. 9B, in such
embodiments of the cassette identification arrangement 410, the
detector 370 of the autoinjector 300 may comprise a plurality of
conventional pogo-pin switches 374n to detect the presence or
absence of the indentations 410i. The coding, detection,
deciphering, and parameter control functions are generally the same
as described above with respect to the tabs 410t.
[0092] Various other embodiments of the indentations 410i of the
cassette identification arrangement 410 can have different depths.
In such embodiments, the autoinjector's pogo-pin switches 374 and
microprocessor 350 can be constructed to allow them to
differentiate between indentations of the different depths by how
far in a pin 374p of the pogo-pin switch 374 is depressed into the
switch by the indentation, to increase the number of possible
different codes.
[0093] In various further embodiments, the cassette identification
arrangement 410 of the cassette may comprise a combination of the
above-described tabs 410t and indentations 410i. The autoinjector,
in such embodiments may then be constructed to include
corresponding push-button and pogo-pin switches 372, 374.
[0094] The codes defined by the tabs 410t and/or indentations 410t
of the cassette identification arrangement 410 communicate
information about the cassette 200 to the autoinjector 300, which
can then use this information to automatically adjust its
programming, etc. For example, but not limitation, one tab 410t or
indentation 410i may define a code that indicates that the cassette
200 contains a drug container filled with 1 mL of a drug and two
tabs 410t or indentations 410i may define a code that indicates
that the cassette 200 contains a drug container filled with 0.5 mL
of a drug. An additional tab 410t or indentation 410i in the same
cassette identification arrangement may provide a code that
identifies the drug and/or characteristics of the drug. In another
example, the code for a training cassette may comprise the presence
of all the possible tabs 410t and/or indentations 410i. In a
further example, the absence of one of the tabs 410t and/or
indentations 410i may define a code for a certain drug. Different
combinations of tabs 410t and/or indentations 410i can be used to
differentiate between different drugs or to indicate the absence of
the drug container, for the purpose of controlling the autoinjector
parameters.
[0095] As shown in FIG. 10A, various other embodiments of the
cassette identification arrangement 410 may comprise one or more
flat, electrically conductive traces or strips 410s provided on the
outer surface of the bottom wall 210b of the outer housing 210. In
such embodiments of the cassette identification arrangement 410, as
shown in FIG. 10B, the detector 370 of the autoinjector 300 can be
constructed with pogo-pin connectors 376 that contact the
conductive strips 410s when the cassette 200 is inserted into the
autoinjector 300. The conductive strips 410s can be molded into the
exterior surface of the cassette's bottom wall 210b, screen-printed
onto that surface, or comprise a separate component, such as a
flex-cable material, affixed to that surface with pressure
sensitive adhesive or any other suitable means.
[0096] In various embodiments, the one or more conductive strips
410s can be operative as a cassette presence sensor, where each of
the conductive strip 410s may operate to close an electrical
circuit of the detector 370 between two pogo-pin connectors 376
when the cassette 200 is mounted on the support surface 301s of the
autoinjector 300. In some embodiments, the conductive strips 410s
can be constructed to form a straight path (e.g., as show in FIG.
10A) to connect inline arranged pogo-pin connectors, or constructed
to form a tortuous path to connect pogo-pin connectors that require
jagged or tortuous path to connect. In other embodiments, the
conductive strips 410s can be constructed to have a specific
electrical resistance, capacitance, inductance, etc., which would
define a code capable of detection via the electrical circuit of
the detector 370, which in turn would communicate the code and,
therefore, the associated cassette information to the
microprocessor 350 of autoinjector 300, such as drug, fill volume,
injection speed, etc.
[0097] As further shown in FIGS. 10A and 10B, various embodiments
of the cassette identification arrangement 410 may combine the one
or more conductive strips 410s with the one or more tabs 410t
(and/or indentions 410i) described earlier. In such embodiments of
the cassette identification arrangement 410, the detector 370 and
microprocessor 350 of the autoinjector 300 can be constructed to
have the appropriate push-button switches 372 and pogo-pin switches
374 (and/or pogo-pin connectors 376). It should be understood,
however, that the cassette identification arrangement 410 may only
comprise the one or more conductive strips 410s.
[0098] As shown in FIG. 11A, various other embodiments of the
cassette identification arrangement 410 may comprise one or more
magnets 410m embedded in the bottom wall 210b of the cassette outer
housing 210 or provided on the exterior or interior surface of the
bottom wall 210b of the cassette outer housing 210. In such
embodiments of the cassette identification arrangement 410, the
detector 370 of the autoinjector 300 (e.g., FIGS. 8B-10B) can be
constructed as a Magnetic Resonance (MR) sensor or other
magnetic-sensing sensor that is activated by the one or more
magnets when the cassette 200 is inserted into the autoinjector
300. The one or more magnets 410m should be of sufficient strength
to activate the MR sensor. The magnet and MR sensor arrangement can
be used alone or combined with any of the other previously
described cassette identification arrangements 410.
[0099] As shown in FIG. 11B, various further embodiments of the
cassette identification arrangement 410 may comprise a
radio-frequency (RF) electromagnetic field (EMF) emitting device
410rf, such as RF identification (RFID) chip. The detector 370 of
the autoinjector 300 (e.g., FIGS. 8B-10B) can be constructed as an
EMF receiving device, such as an RFID chip reader, that is
activated by the RF EMF device 410rf when the cassette 200 is
inserted into the autoinjector 300. The RF EMF device 410rf can be
molded into or attached to the bottom wall 210b of cassette outer
housing 210 or any other suitable portion of the cassette 200 that
allows the RF EMF device 410rf to communicate with the detector 370
of the autoinjector 300.
[0100] As shown in FIG. 11C, various other embodiments of the
cassette identification arrangement 410 may comprise one or more
optical machine-readable (OMR) identifiers 410o. The one or more
OMR identifiers 410o may comprise, without limitation, one or more
bar-code labels, one or more color-coded labels, one or more other
suitable OMR identifiers, or any combination thereof. OMR
identifiers 410o embodied as bar-code labels may comprise, but are
not limited to, 1-dimensional and 2-dimensional matrix codes. The
detector 370 of the autoinjector 300 (e.g., FIGS. 8B-10B), in such
embodiments, can be constructed as an optical scanner. The OMR
identifier 410o may be provided on the exterior surface of the
bottom wall 210b of the cassette's outer housing 210 or any other
suitable portion or area of the cassette 200 that is capable of
interfacing with the detector 370 of the autoinjector 300.
[0101] The RF EMF device 410rf and one or more OMR identifier
labels 410o can be applied to the cassette before or after it is
assembled with the prefilled drug container. This allows the RF EMF
device 410rf and/or one or more OMR identifier labels 410o to
include additional information or programming, such as the date of
manufacture, location of manufacture, expiration date of drug, drug
temperature stabilization time in order to allow the drug to reach
an optimal temperature prior to injection), and autoinjector
verification that the cassette 200 and drug are OEM components.
[0102] As shown in FIG. 11D, various other embodiments of the
cassette identification arrangement 410 may comprise the one or
more magnets 410m, the RF EMF emitter device 410rf, the one or more
OMR identifiers 410o and the tabs 410t (and/or indentations 410i)
described earlier, each defining a portion of the code provided by
the arrangement 410. In such embodiments of the cassette
identification arrangement, the detector 370 of the autoinjector
can be constructed with the appropriate switches, sensors,
receivers, and/or scanners (e.g., FIGS. 8B-10B) to detect the
corresponding cassette elements of the cassette identification
arrangement 410.
[0103] The cassette identification arrangement 410 may also be used
to control aspects of the cassette manufacturing and packaging
processes. FIG. 12 shows a flow chart which shows an example of how
a single production or manufacturing line may be used to assemble
different product lines using the cassette identification
arrangement to control the assembly of the prefilled drug
containers (containing a range of different drugs and/or fill
levels) and then rout the assembled cassettes to the appropriate
packaging stations. Block 500 represents a single manufacturing
line which may comprise a computer controlled manufacturing system
and blocks 502, 504, 506, and 508 may represent four unassembled
cassettes in the line each having its own cassette identification
arrangement configuration (1, 2, 3, or 4) of tabs, indentations,
etc. Each of the unassembled cassettes 502, 504, 506, and 508 are
to be assembled with a drug container having one of four different
drugs (A, B, C, or D) that matches the cassette identification
arrangement configuration (cassette ID configuration). In the
embodiment shown in FIG. 12, the manufacturing system may be
programmed such that cassette ID configuration 1 identifies drug C,
cassette ID configuration 2 identifies drug B, cassette ID
configuration 3 identifies drug D, and cassette ID configuration
identifies drug A.
[0104] In block 510, the manufacturing system of the line
identifies the cassette ID configuration of each of the unassembled
cassettes 502, 504, 506, and 508. For each of the unassembled
cassettes 502, 504, 506, and 508, the system in block 512 selects a
matching one of the drug containers 514, 516, 518, and 518
prefilled with drugs A, B, C, and D, respectively, using the
identified cassette ID and assembles it with the unassembled
cassette 502, 504, 506, and 508. Therefore, in block 512,
unassembled cassette 502 with cassette ID configuration 1 may be
assembled with drug container 518 prefilled with drug C to generate
assembled cassette 522, unassembled cassette 504 with cassette ID
configuration 2 may be assembled with drug container 516 prefilled
with drug B to generate assembled cassette 524, unassembled
cassette 506 with cassette ID configuration 3 may be assembled with
drug container 520 prefilled with drug D to generate assembled
cassette 526, and unassembled cassette 508 with cassette ID
configuration 4 may be assembled with drug container 514 prefilled
with drug A to generate assembled cassette 528.
[0105] In block 530, the manufacturing system sorts assembled
cassettes 522, 524, 526, and 528 using their cassette ID
configurations 1, 2, 3, and 4, respectively, and places them in
packages 532, 534, 536, and 538 for drugs C, B, D, and A,
respectively.
[0106] Referring now to FIG. 13, the autoinjector system 100 may be
constructed to force users to execute the steps of the injection
process in a safe and reliable order, which simplifies the
operation of the autoinjector system 100. By controlling the
sequence of actions performed by the user, the injection process
can be made more reliable. Accordingly, in various embodiments, the
autoinjector system 100 is constructed to force or cause the user
to perform the following steps in sequence: inserting the cassette
200 into the autoinjector 300; preparing the autoinjector system
100 for injection; placing the autoinjector 300 on skin and
starting the injection process; and disposing of the used cassette
200 and storing the autoinjector 300 for future use. Performing
these steps in sequence ensures autoinjector system reliability and
user safety.
[0107] As described above, various embodiments of the autoinjector
300 and cassette 200 can comprise mechanical, electromechanical,
and other structures that provide feedback signals to the
microprocessor (not shown) of the autoinjector 300. The
microprocessor may be programmed with instructions (e.g.,
algorithm), which when executed thereby, allow these signals to be
evaluated by the microprocessor in order to enable the autoinjector
300 to move through discrete logic "states" where the autoinjector
system 100 is in a known configuration.
[0108] Referring now to FIG. 13 in conjunction with the flow chart
of FIG. 14, an embodiment of the decision logic for controlling the
various functions of the autoinjector system 100, will be
described. The decision logic forces the user to perform, in
sequence, the steps of: inserting the cassette 200 into the
autoinjector 300; preparing the autoinjector system 100 for
injection; placing the autoinjector 300 on skin and starting the
injection process; and disposing of the used cassette 200 and
storing the autoinjector 300 for future use.
[0109] Insertion of the Cassette into the Autoinjector
[0110] In block 500 (Off, Door Close, Cassette Out), prior to use,
the autoinjector system 100 may be in a state where the only button
that is active is the one to initiate cassette door opening (eject
button) and all other buttons are deactivated. This may force the
autoinjector system 100 only to respond to a single user action of
pressing the eject button at arrow 502 and all other actions may be
ignored or may not be possible. Once the cassette door 308 of the
autoinjector 300 opens in block 504, the user may insert the
cassette 200 into the door. In various embodiments, the
autoinjector 300 and cassette 200 may comprise certain structures
that allow the insertion of the cassette 200 only in the correct
orientation, such as one or more pins 215 on the cassette 200,
which interacts with a corresponding slot or pin 216 in the
cassette door 308 of the autoinjector 300, as shown in FIG. 14, to
allow insertion only in the correct orientation and prevent
insertion in orientations about the insertion axis (z axis). The
cassette 200 may also have a tapered shape or other structure,
which matches with the cassette door 308 of the autoinjector 300 to
prevent rotation about the x axis.
[0111] While waiting for the user to insert the cassette 200, the
autoinjector 300 may transition to a known state in block 506 (Wait
for Door Close A) where all other actions from the user with the
exception of closing the door may be ignored such as pressing of
start and eject buttons, etc.
[0112] This may force the user to either close the cassette door
308 with a cassette 200 at arrow 508 to proceed with the injection
process, or close the door at arrow 510 without a cassette 200 as
the autoinjector system 100 moves to the previous known state of
block 500. If the user chooses not to perform the required action,
the autoinjector system 100 continues to remain in the same state
in block 512 (Door Open).
[0113] If the user inserts a cassette 200 of either an unknown
configuration and/or a used cassette 200 into the cassette door 308
and closes at arrow 508, the autoinjector system 100 detects this
state using, for example the cassette identification arrangement
described earlier, and does not allow the process to continue to
the next state in block 516. Accordingly, the user is forced to
insert a valid cassette 200 (known configuration and unused) in the
correct orientation into the autoinjector 300 in order to
proceed.
[0114] Preparing the Autoinjector System for Injection
[0115] Once the cassette door 308 of the autoinjector 300 has been
closed with a valid cassette 200, the autoinjector system 100 may
move to an active state in block 514 (Device Wakeup). The next step
by the user in this configuration is to remove the cassette cap 240
at arrow 518. As described above, the autoinjector system 100, in
various embodiments, may be capable of detecting the presence or
absence of the cassette cap 240, and may also capable of monitoring
a transition in the state of a cassette cap remover switch that may
be provided in the autoinjector 300 from presence to absence. This
transition may be used by the autoinjector system 100 to detect the
removal of the cassette cap 240 by the user and moving the
autoinjector system 100 to the state of block 520 (Cap Off). This
may force the user to either remove the cassette cap 240 at arrow
518 to proceed with the injection process, or abort the process by
pressing the eject button at arrow 522, which opens the door at
block 524 (Open Door A) to allow the cassette 200 to be removed and
returns the autoinjector system 100 to the last known state at
block 506 (Wait for Door Close A). If the user chooses not to
perform the required actions, the autoinjector system 100 continues
to remains in the same state at block 515 (Cassette in Sleep).
[0116] To ensure that these actions are truly intended by the user
and not accidentally initiated, the cassette cap removal and abort
process may require a committed action. Cassette cap removal may
have a minimum pull off force and pull off direction such that a
user or patient needs to purposefully hold and pull off the
cassette cap in order to remove the needle shield. In other words,
there is minimum removal force and direction for removal (pulling
straight down) such that the cassette cap cannot be accidentally
removed by normal handling. For the abort process, this may be
achieved by requiring the user to press and hold the eject button
for a set time period at arrow 522 before the eject process is
initiated.
[0117] Place on Skin and Start the Injection Process
[0118] With a valid cassette 200 inserted into the autoinjector
300, the cassette cap 240 removed, and the autoinjector system 100
in the state of block 520 (Cap Off), the user may place the
autoinjector 300 on the injection site (skin) at arrow 526. As
described above, various embodiments of the autoinjector 300 may
include a skin sensor to allow the autoinjector system 100 to
detect proximity to the injection site. Therefore, the autoinjector
system 100 can allow the user to proceed with the injection process
only when the injection site is detected. As described above, the
microprocessor may be programmed with instructions, which allow the
injection site presence to be indicated only when it detects a
continuous positive signal from the skin sensor. This ensures that
the user is committed to the process and has a stable contact with
the injection site in order to move to the state of block 534
(Ready to Inject). As described above, various embodiments of the
cassette cap 240 may have a structure that does not allow it to be
reinserted into the cassette 200 once removed, thereby preventing
the user from reinserting the cassette cap 240 and moving back to
the prior state of block 514 (Device Wakeup).
[0119] This forces the user to either hold the autoinjector 300
with a stable contact at the injection site in order to proceed
with the injection process at block 534 or abort the process by
pressing the eject button at arrow 522, which opens the door at
block 524 to allow cassette removal and returns the autoinjector
system 100 to the last known state after door opening at block 506
(Wait for Door Close A). If no stable signal is obtained at arrow
530, the autoinjector system 100 may continue to remain in the
state of block 520 (Cap Off). If injection site contact is lost at
any point in time, the autoinjector system 100 may return to the
state of block 520 (Cap Off).
[0120] Once the above conditions are met and the autoinjector
system 100 is in the state of block 526 (Ready to Inject), the user
in this configuration activates the injection at arrow 532. Once
initiated, the autoinjector system 100 may reconfirm the cassette
identification arrangement, skin sensor and the like, to confirm
its expected configuration and once confirmed, it may automatically
execute in sequence, needle injection and drug extrusion in block
536 (Injection Progress), (Needle Retraction) in block 538,
(Injection Complete) in block 540, (Plunger Retraction) in block
542 and (Automatic Door Open) in block 544, to allow for cassette
removal and disposal at block 548 (Wait for Door Close B).
Immediately after injection initiation by the user, all other
buttons and switches on the autoinjector 300 may be disabled to
prevent unintentional activation of the buttons by the user during
the injection process.
[0121] During the injection process, the autoinjector system 100
constantly continuously monitors the status of the injection site
contact in block 564. The process may be terminated if at any point
in time there is a loss in injection site contact for a
predetermined time (e.g., the user intentionally removes the
autoinjector 300 from the injection site or adjusts the position in
such a way that a reliable delivery process cannot be ensured). In
addition, autoinjector system 100 may check for various mechanical
errors during the injection process in block 560 (Needle Jam
Error), block 562 (Plunger Jam Error), block 566 (Needle Retraction
Error), block 568 (Device Failure), and block 570 (Cassette
Error).
[0122] If desired, the microprocessor 350 of the autoinjector 300
may be programmed with instructions that, when executed by the
microprocessor 350, enable the autoinjector to control and monitor
the insertion drive 330 to insert the needle 265 at two sequential
speeds. More specifically, the microprocessor 350 can insert the
needle 265 at a first, higher speed to begin the insertion process,
a second, lower speed to finish the insertion process, with the
momentum of the needle 265 and components thereof carrying the
needle 265 to a final stop. In one example, the first speed is
about 0.4 m/s and the second speed is about 0.2 m/s.
[0123] Monitor the Progress of the Injection Process
[0124] An autoinjector drug delivery device 300 configured with a
stall and endpoint detection algorithm is described herein that
allows for variations in the fill of the drug 267, the syringe or
barrel 261, plunger 264, and other components of the autoinjector
300 as set forth above. The algorithm is effective over a range of
situations, configurations, and conditions. A stall or end point
detected by the algorithm during an injection leads the
microprocessor 350 to stop the injection process, retract the
plunger rod 342, and remove the needle 265 from the injection
site.
[0125] The microprocessor 350 of the autoinjector 300 operates
software that tracks the position of the plunger rod 342, such as
by counting signals from the rotary encoder 342 with the optical
sensor 352. The count begins at zero and has an expected end count,
e.g., 2500 counts. The software samples the absolute position of
the plunger rod 342 at set intervals, e.g., 5 mS. Utilizing counts
and timing, the algorithm can determine whether the plunger rod 342
is simply slowing or temporarily stalling vs. stopping or reaching
the end of the barrel 261. Further, the microprocessor 350 can
compare readings to past samples and the algorithm can be
configured to utilize the past samples, which can provide an
expected end point, to determine when to stop the injection,
retract the plunger rod 342, remove the needle 265, and end the
injection process.
[0126] A flowchart for such an algorithm is shown in FIG. 15.
Generally, the microprocessor 350 follows the logic of the
algorithm to sample counts of the signals from the encoder 346 to
determine the position of the plunger rod 342 and, therefore, the
plunger 264 during the injection process. By setting the values of
the sample intervals, a number of counts indicating movement, and
associations therebetween, the algorithm allows the microprocessor
350 to determine whether the plunger as stalled or reached an
expected end point.
[0127] At block 600, the drug extrusion process starts and the
algorithm begins at count 0. After a predetermined interval has
passed (e.g., 5 mS), in block 602 the algorithm takes a sample of
the injection position based on counts of the rotary encoder 346
with the optical sensor 352. In block 604, the algorithm determines
if the sample indicates movement of the plunger rod 342. If there
is movement, the algorithm returns to block 602 to take another
sample of the position of the plunger rod. If there is no movement,
then in block 606, the algorithm determines if there has been
movement less than a count of m signals detected by the encoder 346
has been detected within the last n number of samples. If no, the
algorithm loops back to block 602 and the plunger position is
re-sampled. Alternatively, if total movement is less than m within
last n samples, then in block 608, the algorithm compares the total
count number to an expected end count x. If the total count number
is not near to or is less than the end count x, the algorithm
determines that the injection is incomplete and proceeds to block
610. In block 610, if the end count is not near, then `value<m
within last n samples` can be rechecked with different values m and
n. This is to check for stalls during extrusion due to the
variations and conditions set forth above. If a stall is detected
during extrusion, the motor is stopped, and the algorithm ends in
block 612, Otherwise, the algorithm continues back to block 602 to
re-samples plunger position. Back to block 608, if the total count
number is near to or is greater than the end count x, the algorithm
moves to block 614, and determines that a full dose of the drug 267
has been dispensed.
[0128] With this configuration, selection of the value of n
determines the sensitivity of the speed at which a stall is
detected. For example, if a stall can be detected between [n and
(n+1)] samples without movement detected, then a stall in an
injection process having a duration between [(n*5 mS) and ((n+1)*5
mS)] can be detected. The range of speeds (counts per second) at
which the plunger is moving when a stall is detected is given by
[(1000*m)/((n+1)*5 mS) and (1000*m)/((n)*5 mS)] where 1000 is the
conversion factor 1000 mS/S and 5 mS is the sampling rate.
TABLE-US-00001 TABLE 1 Stall Detection Randes for m = 1 Stall
detection Stall detection n time range [mS] speed range [cnt/sec]
10 50 55 18.2 20.0 9 45 50 20.0 22.2 8 40 45 22.2 25.0 7 35 40 25.0
28.6 6 30 35 28.6 33.3 5 25 30 33.3 40.0 4 20 25 40.0 50.0 3 15 20
50.0 66.7 2 10 15 66.7 100.0
[0129] When the detection ranges shown in Table 1 are applied to
actual data from an injection operation of an autoinjector device
300, as illustrated in FIG. 16, it can be determined how effective
the detection algorithm can be. As shown, the injection speed is
generally constant at about 225 cnt/s for about 8.1 seconds until
the plunger 264 reaches the end of the syringe barrel 261.
Thereafter, the speed falls off steadily until the plunger 264
cannot compress anymore, which happens at a little over 8.8
seconds. A little before 9 seconds, the plunger rod 342 starts to
embed within the plunger 264 is again stopped at 9.2 seconds.
Driving the plunger rod 342 further after 9.2 seconds could break
the glass of the syringe barrel 261. Ideally, an injection
operation fully compresses the plunger 264 without embedding it
therein. As such, in this example, an ideal operation would stop at
around 8.8 seconds. The graph shows the range of detection if n=2
and m=1.
[0130] If desired, the microprocessor 350 can further be configured
to maintain a generally constant extrusion speed to continuously
adjust for conditions or configurations of a particular injector
300. The algorithm first set a current limit for a particular speed
target, based on the drug 267, injector 300, user preference, and
combinations thereof. While the microprocessor 350 samples the
plunger rod 342 position, as set forth above, the microprocessor
350 compares the movement of a current sample to a past sample or
samples to determine a rate and change. If the speed is over a
target, the current limit is adjusted lower. If the speed is under
a target, the current limit is adjusted higher.
[0131] Disposal of the Used Cassette and Storing the Autoinjector
for Future Use
[0132] Once the injection process is complete and the autoinjector
system 100 is in the state of block 548 (Wait for Door Close B),
the user is expected to remove and disposed of the used cassette
200 and close the cassette door 308 of the autoinjector 300 at
arrow 550. In order to force the user to do this, the autoinjector
system 100 logic may be configured so that the user cannot close
the cassette door 308 of the autoinjector 300 with a cassette 200
in the state of block 548. If door closure is attempted at arrow
552, the autoinjector system 100 may detect the cassette 200 and
immediately reopen the door at block 554. This may force the user
to close the cassette door 308 without a cassette 200 in order for
the autoinjector system 100 to move to the state of block 550 (Off)
and store the autoinjector 300 for future use. If the user chooses
not to perform the required action, the autoinjector system 100 may
continue to remain in the same state in block 556 (Door Open Sleep
B).
[0133] Drug Information
[0134] The above description describes various assemblies, devices,
and methods for use with a drug delivery device. It should be clear
that the assemblies, drug delivery devices, or methods can further
comprise use of a drug or medicament listed below with the caveat
that the following list should neither be considered to be all
inclusive nor limiting. The drug or medicament will be contained in
a reservoir. In some instances, the reservoir is a primary
container that is either filled or pre-filled for treatment with
the drug or medicament. The primary container can be a cartridge or
a pre-filled syringe. As used herein, the term drug can be used
interchangeably with other similar types of phrases and can be used
to mean any type of medicament, therapeutic or non-therapeutic
injectable such as traditional and non-traditional pharmaceuticals,
nutraceuticals, nutritional supplements, prodrugs (e.g., a compound
or molecule which is administered in an inactive or less active
state but is cleaved/processed to form the active drug inside the
recipient), biologics, biologically active compounds, biologically
active molecules, biologically active agents, etc.
[0135] The drug container of the cassette may be filled for
treatment or be prefilled with a pharmaceutical product, such as an
erythropoiesis stimulating agent (ESA), which may be in a liquid or
a lyophilized form. An ESA can be an erythropoiesis stimulating
protein. As used herein, "erythropoiesis stimulating protein" means
any protein that directly or indirectly causes activation of the
erythropoietin receptor, for example, by binding to and causing
dimerization of the receptor. Erythropoiesis stimulating proteins
comprise erythropoietin and variants, analogs, or derivatives
thereof that bind to and activate erythropoietin receptor;
antibodies that bind to erythropoietin receptor and activate the
receptor; or peptides that bind to and activate erythropoietin
receptor. Erythropoiesis stimulating proteins comprise, but are not
limited to, epoetin alfa, epoetin beta, epoetin delta, epoetin
omega, epoetin iota, epoetin zeta, and analogs thereof, pegylated
erythropoietin, carbamylated erythropoietin, mimetic peptides
(comprising EMP1/Hematide), and mimetic antibodies. Exemplary
erythropoiesis stimulating proteins comprise erythropoietin,
darbepoetin, erythropoietin agonist variants, and peptides or
antibodies that bind and activate erythropoietin receptor.
[0136] The term erythropoiesis stimulating protein comprises
without limitation Epogen.RTM. (epoetin alfa), Aranesp.RTM.
(darbepoetin alfa), Dynepo.RTM. (epoetin delta), Mircera.RTM.
(methyoxy polyethylene glycol-epoetin beta), Hematide.TM.
(peginesatide), MRK-2578, INS-22, Retacrit.RTM. (epoetin zeta),
Neorecormon.RTM. (epoetin beta), Silapo.TM. (epoetin zeta),
Binocrit.RTM. (epoetin alfa), epoetin alfa Hexal, Abseamed.TM.
(epoetin alfa), Ratioepo.TM. (epoetin theta), Eporatio.TM. (epoetin
theta), Biopoin.TM. (epoetin theta), epoetin alfa, epoetin beta,
epoetin zeta, epoetin theta, and epoetin delta.
[0137] The term erythropoiesis stimulating protein further
comprises the molecules or variants or analogs as disclosed in the
following patents or patent applications, which are each herein
incorporated by reference in its entirety: U.S. Pat. Nos.
4,703,008; 5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349;
5,767,078; 5,773,569; 5,830,851; 5,856,298; 5,955,422; 5,986,047;
6,030,086; 6,310,078; 6,391,633; 6,583,272; 6,586,398; 6,900,292;
6,750,369; 7,030,226; 7,084,245; and 7,271,689; U.S. Publ. Nos.
2002/0155998; 2003/0077753; 2003/0082749; 2003/0143202;
2003/0215444; 2004/0009902; 2004/0071694; 2004/0091961;
2004/0143857; 2004/0157293; 2004/0175379; 2004/0175824;
2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914;
2005/0026834; 2005/0096461; 2005/0107297; 2005/0107591;
2005/0124045; 2005/0124564; 2005/0137329; 2005/0142642;
2005/0143292; 2005/0153879; 2005/0158822; 2005/0158832;
2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;
2005/0202538; 2005/0227289; 2005/0244409; 2006/0040858;
2006/0088906; and 2006/0111279; and PCT Publ. Nos. WO 91/05867; WO
95/05465; WO 96/40772; WO 99/66054; WO 00/24893; WO 01/81405; WO
00/61637; WO 01/36489; WO 02/014356; WO 02/19963; WO 02/20034; WO
02/49673; WO 02/085940; WO 03/029291; WO 2003/055526; WO
2003/084477; WO 2003/094858; WO 2004/002417; WO 2004/002424; WO
2004/009627; WO 2004/024761; WO 2004/033651; WO 2004/035603; WO
2004/043382; WO 2004/101600; WO 2004/101606; WO 2004/101611; WO
2004/106373; WO 2004/018667; WO 2005/001025; WO 2005/001136; WO
2005/021579; WO 2005/025606; WO 2005/032460; WO 2005/051327; WO
2005/063808; WO 2005/063809; WO 2005/070451; WO 2005/081687; WO
2005/084711; WO 2005/103076; WO 2005/100403; WO 2005/092369; WO
2006/50959; WO 2006/02646; WO 2006/29094; and WO 2007/136752.
[0138] Alternatively, the drug container of the cassette may also
be filled for treatment or be prefilled with other products.
Examples of other pharmaceutical products that may be used may
comprise, but are not limited to, therapeutics such as a biological
(e.g., Enbrel.RTM. (etanercept, TNF-receptor/Fc fusion protein, TNF
blocker), anti-TNF antibodies such as adalimumab, infliximab,
certolizumab pegol, and golimumab; anti-IL-12 antibodies such as
ustekinumab, other Fc fusions such as CTL4A:Fc also known as
abacept; Neulasta.RTM. (pegylated filgastrim, pegylated G-CSF,
pegylated hu-met-G-CSF), Neupogen.RTM. (filgrastim, G-CSF,
hu-met-G-CSF), Nplate.RTM. (romiplostim), Vectibix.RTM.
(panitumumab), Sensipar.RTM. (cinacalcet), and Xgeva.RTM. and
Prolia.RTM. (each denosamab, AMG 162); as well as other small
molecule drugs, a therapeutic antibodies, a polypeptides, proteins
or other chemicals, such as an iron (e.g., ferumoxytol, iron
dextrans, ferric glyconate, and iron sucrose). The therapeutic may
be in liquid form, or reconstituted from lyophilized form.
[0139] Among particular illustrative proteins that can be used in
the drug container of the cassette are antibodies, peptibodies,
pegylated proteins, polypeptides, and related proteins (comprising
fusions, fragments, analogs, variants or derivatives thereof) for
example, proteins that specifically bind to: OPGL; IL-4 receptor;
interleukin 1-receptor 1 ("IL1-R1"); angiopoietin-2 (Ang2); NGF;
CD22; IGF-1; B-7 related protein 1 (B7RP1); IL-15; IL-17 Receptor
A: IFN gamma; TALL-1; parathyroid hormone ("PTH"); thrombopoietin
receptor ("TPO-R"); hepatocyte growth factor ("HGF"); TRAIL-R2;
Activin A; TGF-beta; amyloid-beta; c-Kit; .alpha.4.beta.7: and
IL-23 or one of its subunits; and other therapeutic proteins.
[0140] The drug container of the cassette may also be filled for
treatment or be prefilled with OPGL specific antibodies,
peptibodies, and related proteins, and the like (also referred to
as RANKL specific antibodies, peptibodies and the like), comprising
fully humanized and human OPGL specific antibodies, particularly
fully humanized monoclonal antibodies, comprising but not limited
to the antibodies described in PCT Publ. No. WO 03/002713,
particularly those having the sequences set forth therein,
particularly, but not limited to, those denoted therein: 9H7; 18B2;
2D8; 2E11; 16E1; and 22B3, comprising the OPGL specific antibodies
having either the light chain of SEQUENCE IDENTIFICATION NUMBER: 2
therein as set forth in FIG. 2 therein and/or the heavy chain of
SEQUENCE IDENTIFICATION NUMBER:4 therein, as set forth in FIG. 4
therein.
[0141] The drug container of the cassette may also be filled for
treatment or be prefilled with myostatin binding proteins,
peptibodies, and related proteins, and the like, comprising
myostatin specific peptibodies, particularly those described in US
Publ. No. 2004/0181033 and PCT Publ. No. WO 2004/058988,
particularly in parts pertinent to myostatin specific peptibodies,
comprising but not limited to peptibodies of the mTN8-19 family,
comprising those of SEQUENCE IDENTIFICATION NUMBERS: 305-351,
comprising TN8-19-1 through TN8-19-40, TN8-19 coni and TN8-19 con2;
peptibodies of the mL2 family of SEQUENCE IDENTIFICATION NUMBERS:
357-383 therein; the mL15 family of SEQUENCE IDENTIFICATION
NUMBERS: 384-409; the mL17 family of SEQUENCE IDENTIFICATION
NUMBERS: 410-438 therein; the mL20 family of SEQUENCE
IDENTIFICATION NUMBERS: 439-446 therein; the mL21 family of
SEQUENCE IDENTIFICATION NUMBERS: 447-452 therein; the mL24 family
of SEQUENCE IDENTIFICATION NUMBERS: 453-454 therein; and those of
SEQUENCE IDENTIFICATION NUMBERS: 615-631 therein, as disclosed in
the foregoing publication.
[0142] The drug container of the cassette may also be filled for
treatment or be prefilled with IL-4 receptor specific antibodies,
peptibodies, and related proteins, and the like, particularly those
that inhibit activities mediated by binding of IL-4 and/or IL-13 to
the receptor, comprising those described in PCT Publ. No. WO
2005/047331 or PCT Appl. No. PCT/US2004/03742 and in US Publ. No.
2005/112694, which are incorporated herein by reference in their
entirety particularly in parts pertinent to IL-4 receptor specific
antibodies, particularly such antibodies as are described therein,
particularly, and without limitation, those designated therein:
L1H1; L1H2; L1H3; L1H4; L1H5; L1H6; L1H7; L1H8; L1H9; L1H10; L1H11;
L2H1; L2H2; L2H3; L2H4; L2H5; L2H6; L2H7; L2H8; L2H9; L2H10; L2H11;
L2H12; L2H13; L2H14; L3H1; L4H1; L5H1; L6H1, each of which is
individually and specifically incorporated by reference herein in
its entirety fully as disclosed in the foregoing publication.
[0143] The drug container of the cassette may also be filled for
treatment or be prefilled with IL1-R1 specific antibodies,
peptibodies, and related proteins, and the like, comprising but not
limited to those described in U.S. Publ. No. 2004/097712A1, which
is incorporated herein by reference in its entirety in parts
pertinent to IL1-R1 specific binding proteins, monoclonal
antibodies in particular, especially, without limitation, those
designated therein: 15CA, 26F5, 27F2, 24E12, and 10H7, each of
which is individually and specifically incorporated by reference
herein in its entirety fully as disclosed in the aforementioned
U.S. publication.
[0144] The drug container of the cassette may also be filled for
treatment or be prefilled with Ang2 specific antibodies,
peptibodies, and related proteins, and the like, comprising but not
limited to those described in PCT Publ. No. WO 03/057134 and U.S.
Publ No. 2003/0229023, each of which is incorporated herein by
reference in its entirety particularly in parts pertinent to Ang2
specific antibodies and peptibodies and the like, especially those
of sequences described therein and comprising but not limited to:
L1(N); L1(N) WT; L1(N) 1K WT; 2xL1(N); 2xL1(N) WT; Con4 (N), Con4
(N) 1K WT, 2xCon4 (N) 1K; L1C; L1C 1K; 2xL1C; Con4C; Con4C 1K;
2xCon4C 1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N);
TN8-14 (N); Con 1 (N), also comprising anti-Ang 2 antibodies and
formulations such as those described in PCT Publ. No. WO
2003/030833 which is incorporated herein by reference in its
entirety as to the same, particularly Ab526; Ab528; Ab531; Ab533;
Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551;
Ab553; Ab555; Ab558; Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK;
AbG1D4; AbGC1E8; AbH1C12; AbIA1; AbIF; AbIK, AbIP; and AbIP, in
their various permutations as described therein, each of which is
individually and specifically incorporated by reference herein in
its entirety fully as disclosed in the foregoing publication.
[0145] The drug container of the cassette may also be filled for
treatment or be prefilled with NGF specific antibodies,
peptibodies, and related proteins, and the like comprising, in
particular, but not limited to those described in US Publ. No.
2005/0074821 and U.S. Pat. No. 6,919,426, which are incorporated
herein by reference in their entirety particularly as to
NGF-specific antibodies and related proteins in this regard,
comprising in particular, but not limited to, the NGF-specific
antibodies therein designated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11,
each of which is individually and specifically incorporated by
reference herein in its entirety fully as disclosed in the
foregoing publication.
[0146] The drug container of the cassette may also be filled for
treatment or be prefilled with CD22 specific antibodies,
peptibodies, and related proteins, and the like, such as those
described in U.S. Pat. No. 5,789,554, which is incorporated herein
by reference in its entirety as to CD22 specific antibodies and
related proteins, particularly human CD22 specific antibodies, such
as but not limited to humanized and fully human antibodies,
comprising but not limited to humanized and fully human monoclonal
antibodies, particularly comprising but not limited to human CD22
specific IgG antibodies, such as, for instance, a dimer of a
human-mouse monoclonal hLL2 gamma-chain disulfide linked to a
human-mouse monoclonal hLL2 kappa-chain, comprising, but limited
to, for example, the human CD22 specific fully humanized antibody
in Epratuzumab, CAS registry number 501423-23-0;
[0147] The drug container of the cassette may also be filled for
treatment or be prefilled with IGF-1 receptor specific antibodies,
peptibodies, and related proteins, and the like, such as those
described in PCT Publ. No. WO 06/069202, which is incorporated
herein by reference in its entirety as to IGF-1 receptor specific
antibodies and related proteins, comprising but not limited to the
IGF-1 specific antibodies therein designated L1H1, L2H2, L3H3,
L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13,
L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21,
L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29,
L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37,
L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45,
L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and
IGF-1R-binding fragments and derivatives thereof, each of which is
individually and specifically incorporated by reference herein in
its entirety fully as disclosed in the foregoing International
Publication.
[0148] Also among non-limiting examples of anti-IGF-1R antibodies
for use in the methods and compositions of the present invention
are each and all of those described in: (i) US Publ. No.
2006/0040358 (published Feb. 23, 2006), 2005/0008642 (published
Jan. 13, 2005), 2004/0228859 (published Nov. 18, 2004), comprising
but not limited to, for instance, antibody 1A (DSMZ Deposit No. DSM
ACC 2586), antibody 8 (DSMZ Deposit No. DSM ACC 2589), antibody 23
(DSMZ Deposit No. DSM ACC 2588) and antibody 18 as described
therein; (ii) PCT Publ. No. WO 06/138729 (published Dec. 28, 2006)
and WO 05/016970 (published Feb. 24, 2005), and Lu et al., 2004, J
Biol. Chem. 279:2856-65, comprising but not limited to antibodies
2F8, A12, and IMC-A12 as described therein; (iii) PCT Publ. No. WO
07/012614 (published Feb. 1, 2007), WO 07/000328 (published Jan. 4,
2007), WO 06/013472 (published Feb. 9, 2006), WO 05/058967
(published Jun. 30, 2005), and WO 03/059951 (published Jul. 24,
2003); (iv) US Publ. No. 2005/0084906 (published Apr. 21, 2005),
comprising but not limited to antibody 7C10, chimaeric antibody
C7C10, antibody h7C10, antibody 7H2M, chimaeric antibody *7C10,
antibody GM 607, humanized antibody 7C10 version 1, humanized
antibody 7C10 version 2, humanized antibody 7C10 version 3, and
antibody 7H2HM, as described therein; (v) US Publ. Nos.
2005/0249728 (published Nov. 10, 2005), 2005/0186203 (published
Aug. 25, 2005), 2004/0265307 (published Dec. 30, 2004), and
2003/0235582 (published Dec. 25, 2003) and Maloney et al., 2003,
Cancer Res. 63:5073-83, comprising but not limited to antibody
EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164
v1.1, huEM164 v1.2, and huEM164 v1.3 as described therein; (vi)
U.S. Pat. No. 7,037,498 (issued May 2, 2006), US Publ. Nos.
2005/0244408 (published Nov. 30, 2005) and 2004/0086503 (published
May 6, 2004), and Cohen, et al., 2005, Clinical Cancer Res.
11:2063-73, e.g., antibody CP-751,871, comprising but not limited
to each of the antibodies produced by the hybridomas having the
ATCC accession numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791,
PTA-2789, PTA-2793, and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1,
4.9.2, and 4.17.3, as described therein; (vii) US Publ. Nos.
2005/0136063 (published Jun. 23, 2005) and 2004/0018191 (published
Jan. 29, 2004), comprising but not limited to antibody 19D12 and an
antibody comprising a heavy chain encoded by a polynucleotide in
plasmid 15H12/19D12 HCA (.gamma.4), deposited at the ATCC under
number PTA-5214, and a light chain encoded by a polynucleotide in
plasmid 15H12/19D12 LCF (.kappa.), deposited at the ATCC under
number PTA-5220, as described therein; and (viii) US Publ. No.
2004/0202655 (published Oct. 14, 2004), comprising but not limited
to antibodies PINT-6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6,
PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4,
PINT-11A5, PINT-11A7, PINT-11Al2, PINT-12A1, PINT-12A2, PINT-12A3,
PINT-12A4, and PINT-12A5, as described therein; each and all of
which are herein incorporated by reference in their entireties,
particularly as to the aforementioned antibodies, peptibodies, and
related proteins and the like that target IGF-1 receptors.
[0149] The drug container of the cassette may also be filled for
treatment or be prefilled with B-7 related protein 1 specific
antibodies, peptibodies, related proteins and the like ("B7RP-1,"
also is referred to in the literature as B7H2, ICOSL, B7h, and
CD275), particularly B7RP-specific fully human monoclonal IgG2
antibodies, particularly fully human IgG2 monoclonal antibody that
binds an epitope in the first immunoglobulin-like domain of B7RP-1,
especially those that inhibit the interaction of B7RP-1 with its
natural receptor, ICOS, on activated T cells in particular,
especially, in all of the foregoing regards, those disclosed in
U.S. Publ. No. 2008/0166352 and PCT Publ. No. WO 07/011941,
comprising but not limited to antibodies designated therein as
follow: 16H (having light chain variable and heavy chain variable
sequences SEQUENCE IDENTIFICATION NUMBER:1 and SEQUENCE
IDENTIFICATION NUMBER:7 respectively therein); 5D (having light
chain variable and heavy chain variable sequences SEQUENCE
IDENTIFICATION NUMBER:2 and SEQUENCE IDENTIFICATION NUMBER:9
respectively therein); 2H (having light chain variable and heavy
chain variable sequences SEQUENCE IDENTIFICATION NUMBER:3 and
SEQUENCE IDENTIFICATION NUMBER:10 respectively therein); 43H
(having light chain variable and heavy chain variable sequences
SEQUENCE IDENTIFICATION NUMBER:6 and SEQUENCE IDENTIFICATION
NUMBER:14 respectively therein); 41H (having light chain variable
and heavy chain variable sequences SEQUENCE IDENTIFICATION NUMBER:5
and SEQUENCE IDENTIFICATION NUMBER:13 respectively therein); and
15H (having light chain variable and heavy chain variable sequences
SEQUENCE IDENTIFICATION NUMBER:4 and SEQUENCE IDENTIFICATION
NUMBER:12 respectively therein).
[0150] The drug container of the cassette may also be filled for
treatment or be prefilled with IL-15 specific antibodies,
peptibodies, and related proteins, and the like, such as, in
particular, humanized monoclonal antibodies, particularly
antibodies such as those disclosed in U.S. Publ. Nos. 2003/0138421;
2003/023586; and 2004/0071702; and U.S. Pat. No. 7,153,507, each of
which is incorporated herein by reference in its entirety as to
IL-15 specific antibodies and related proteins, comprising
peptibodies, comprising particularly, for instance, but not limited
to, HuMax IL-15 antibodies and related proteins, such as, for
instance, 146B7.
[0151] The drug container of the cassette may also be filled for
treatment or be prefilled with pharmaceutical compositions
comprising antagonistic human monoclonal antibodies against human
IL-17 Receptor A. The characterization, cloning, and preparation of
IL-17 Receptor A are described in U.S. Pat. No. 6,072,033, issued
Jun. 6, 2000. The amino acid sequence of the human IL-17RA is shown
in SEQUENCE IDENTIFICATION NUMBER:10 of U.S. Pat. No. 6,072,033
(GenBank accession number NM 014339). Such antibodies may comprise
those disclosed in WO 2008/054603 or the antibodies claimed in U.S.
Pat. No. 7,767,206, issued Aug. 3, 2010, and in U.S. Ser. No.
11/906,094.
[0152] The drug container of the cassette may also be filled for
treatment or be prefilled with IFN gamma specific antibodies,
peptibodies, and related proteins and the like, especially human
IFN gamma specific antibodies, particularly fully human anti-IFN
gamma antibodies, such as, for instance, those described in US
Publ. No. 2005/0004353 as to IFN gamma specific antibodies,
particularly, for example, the antibodies therein designated 1118;
1118*; 1119; 1121; and 1121*. The entire sequences of the heavy and
light chains of each of these antibodies, as well as the sequences
of their heavy and light chain variable regions and complementarity
determining regions as disclosed in the foregoing US Publication
and in Thakur et al., Mol. Immunol. 36:1107-1115 (1999). Specific
antibodies comprise those having the heavy chain of SEQUENCE
IDENTIFICATION NUMBER: 17 and the light chain of SEQUENCE
IDENTIFICATION NUMBER:18; those having the heavy chain variable
region of SEQUENCE IDENTIFICATION NUMBER:6 and the light chain
variable region of SEQUENCE IDENTIFICATION NUMBER:8; those having
the heavy chain of SEQUENCE IDENTIFICATION NUMBER:19 and the light
chain of SEQUENCE IDENTIFICATION NUMBER:20; those having the heavy
chain variable region of SEQUENCE IDENTIFICATION NUMBER:10 and the
light chain variable region of SEQUENCE IDENTIFICATION NUMBER:12;
those having the heavy chain of SEQUENCE IDENTIFICATION NUMBER:32
and the light chain of SEQUENCE IDENTIFICATION NUMBER:20; those
having the heavy chain variable region of SEQUENCE IDENTIFICATION
NUMBER:30 and the light chain variable region of SEQUENCE
IDENTIFICATION NUMBER:12; those having the heavy chain sequence of
SEQUENCE IDENTIFICATION NUMBER:21 and the light chain sequence of
SEQUENCE IDENTIFICATION NUMBER:22; those having the heavy chain
variable region of SEQUENCE IDENTIFICATION NUMBER:14 and the light
chain variable region of SEQUENCE IDENTIFICATION NUMBER:16; those
having the heavy chain of SEQUENCE IDENTIFICATION NUMBER:21 and the
light chain of SEQUENCE IDENTIFICATION NUMBER:33; and those having
the heavy chain variable region of SEQUENCE IDENTIFICATION
NUMBER:14 and the light chain variable region of SEQUENCE
IDENTIFICATION NUMBER:31, as disclosed in the foregoing US
Publication. A specific antibody contemplated is antibody 1119 as
disclosed in foregoing US Publication and having a complete heavy
chain of SEQUENCE IDENTIFICATION NUMBER:17 as disclosed therein and
having a complete light chain of SEQUENCE IDENTIFICATION NUMBER:18
as disclosed therein.
[0153] The drug container of the cassette may also be filled for
treatment or be prefilled with TALL-1 specific antibodies,
peptibodies, and related proteins, and the like, and other TALL
specific binding proteins, such as those described in U.S. Publ.
Nos. 2003/0195156 and 2006/0135431, each of which is incorporated
herein by reference in its entirety as to TALL-1 binding proteins,
particularly the molecules of Tables 4 and 5B therein, each of
which is individually and specifically incorporated by reference
herein in its entirety fully as disclosed in the foregoing US
Publications.
[0154] The drug container of the cassette may also be filled for
treatment or be prefilled with PTH specific antibodies,
peptibodies, and related proteins, and the like, such as those
described in U.S. Pat. No. 6,756,480, which is incorporated herein
by reference in its entirety, particularly in parts pertinent to
proteins that bind PTH.
[0155] The drug container of the cassette may also be filled for
treatment or be prefilled with TPO-R specific antibodies,
peptibodies, and related proteins, and the like, such as those
described in U.S. Pat. No. 6,835,809, which is herein incorporated
by reference in its entirety, particularly in parts pertinent to
proteins that bind TPO-R.
[0156] The drug container of the cassette may also be filled for
treatment or be prefilled with HGF specific antibodies,
peptibodies, and related proteins, and the like, comprising those
that target the HGF/SF:cMet axis (HGF/SF:c-Met), such as the fully
human monoclonal antibodies that neutralize hepatocyte growth
factor/scatter (HGF/SF) described in US Publ. No. 2005/0118643 and
PCT Publ. No. WO 2005/017107, huL2G7 described in U.S. Pat. No.
7,220,410 and OA-5d5 described in U.S. Pat. Nos. 5,686,292 and
6,468,529 and in PCT Publ. No. WO 96/38557, each of which is
incorporated herein by reference in its entirety, particularly in
parts pertinent to proteins that bind HGF.
[0157] The drug container of the cassette may also be filled for
treatment or be prefilled with TRAIL-R2 specific antibodies,
peptibodies, related proteins and the like, such as those described
in U.S. Pat. No. 7,521,048, which is herein incorporated by
reference in its entirety, particularly in parts pertinent to
proteins that bind TRAIL-R2.
[0158] The drug container of the cassette may also be filled for
treatment or be prefilled with Activin A specific antibodies,
peptibodies, related proteins, and the like, comprising but not
limited to those described in US Publ. No. 2009/0234106, which is
herein incorporated by reference in its entirety, particularly in
parts pertinent to proteins that bind Activin A.
[0159] The drug container of the cassette may also be filled for
treatment or be prefilled with TGF-beta specific antibodies,
peptibodies, related proteins, and the like, comprising but not
limited to those described in U.S. Pat. No. 6,803,453 and US Publ.
No. 2007/0110747, each of which is herein incorporated by reference
in its entirety, particularly in parts pertinent to proteins that
bind TGF-beta.
[0160] The drug container of the cassette may also be filled for
treatment or be prefilled with amyloid-beta protein specific
antibodies, peptibodies, related proteins, and the like, comprising
but not limited to those described in PCT Publ. No. WO 2006/081171,
particularly in parts pertinent to proteins that bind amyloid-beta
proteins. One antibody contemplated is an antibody having a heavy
chain variable region comprising SEQUENCE IDENTIFICATION NUMBER: 8
and a light chain variable region having SEQUENCE IDENTIFICATION
NUMBER: 6 as disclosed in the International Publication.
[0161] The drug container of the cassette may also be filled for
treatment or be prefilled with c-Kit specific antibodies,
peptibodies, related proteins, and the like, comprising but not
limited to those described in Publ. No. 2007/0253951, which is
incorporated herein by reference in its entirety, particularly in
parts pertinent to proteins that bind c-Kit and/or other stem cell
factor receptors.
[0162] The drug container of the cassette may also be filled for
treatment or be prefilled with OX40L specific antibodies,
peptibodies, related proteins, and the like, comprising but not
limited to those described in U.S. application Ser. No. 11/068,289,
which is incorporated herein by reference in its entirety,
particularly in parts pertinent to proteins that bind OX40L and/or
other ligands of the OX040 receptor.
[0163] The drug container of the cassette may also be filled for
treatment or be prefilled with other exemplary proteins comprising
but are not limited to Activase.RTM. (Alteplase, tPA); Aranesp.RTM.
(Darbepoetin alfa), Epogen.RTM. (Epoetin alfa, or erythropoietin);
Avonex.RTM. (Interferon beta-1a); Bexxar.RTM. (Tositumomab,
anti-CD22 monoclonal antibody); Betaseron.RTM. (Interferon-beta);
Campath.RTM. (Alemtuzumab, anti-CD52 monoclonal antibody);
Dynepo.RTM. (Epoetin delta); Velcade.RTM. (bortezomib); MLN0002
(anti-.alpha.487 mAb); MLN1202 (anti-CCR2 chemokine receptor mAb);
Enbrel.RTM. (etanercept, TNF-receptor/Fc fusion protein, TNF
blocker); Eprex.RTM. (Epoetin alfa); Erbitux.RTM. (Cetuximab,
anti-EGFR/HER1/c-ErbB-1); Genotropin.RTM. (Somatropin, Human Growth
Hormone); Herceptin.RTM. (Trastuzumab, anti-HER2/neu (erbB2)
receptor mAb); Humatrope.RTM. (Somatropin, Human Growth Hormone);
Humira.RTM. (Adalimumab); Insulin in Solution; Infergen.RTM.
(Interferon Alfacon-1); Natrecor.RTM. (nesiritide; recombinant
human B-type natriuretic peptide (hBNP); Kineret.RTM. (Anakinra),
Leukine.RTM. (Sargamostim, rhuGM-CSF); LymphoCide.RTM.
(Epratuzumab, anti-CD22 mAb); Lymphostat B.RTM. (Belimumab,
anti-BlyS mAb); Metalyse.RTM. (Tenecteplase, t-PA analog);
Mircera.RTM. (methoxy polyethylene glycol-epoetin beta);
Mylotarg.RTM. (Gemtuzumab ozogamicin); Raptiva.RTM. (efalizumab);
Cimzia.RTM. (certolizumab pegol, CDP 870); Soliris.TM.
(Eculizumab); Pexelizumab (Anti-05 Complement); MEDI-524
(Numax.RTM.); Lucentis.RTM. (Ranibizumab); 17-1A (Edrecolomab,
Panorex.RTM.); Trabio.RTM. (lerdelimumab); TheraCim hR3
(Nimotuzumab); Omnitarg (Pertuzumab, 2C4); Osidem.RTM. (IDM-1);
OvaRex.RTM. (B43.13); Nuvion.RTM. (visilizumab); Cantuzumab
mertansine (huC242-DM1); NeoRecormon.RTM. (Epoetin beta);
Neumega.RTM. (Oprelvekin, Human Interleukin-11); Neulasta.RTM.
(Pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G-CSF);
Neupogen.RTM. (Filgrastim, G-CSF, hu-MetG-CSF); Orthoclone
OKT3.RTM. (Muromonab-CD3, anti-CD3 monoclonal antibody),
Procrit.RTM. (Epoetin alfa); Remicade.RTM. (Infliximab,
anti-TNF.alpha. monoclonal antibody), Reopro.RTM. (Abciximab,
anti-GP IIb/IIia receptor monoclonal antibody), Aclemra.RTM.
(anti-IL6 Receptor mAb), Avastin.RTM. (Bevacizumab), HuMax-CD4
(zanolimumab), Rituxan.RTM. (Rituximab, anti-CD20 mAb);
Tarceva.RTM. (Erlotinib); Roferon-A0-(Interferon alfa-2a);
Simulect.RTM. (Basiliximab); Prexige.RTM. (lumiracoxib);
Synagis.RTM. (Palivizumab); 146B7-CHO (anti-IL15 antibody, see U.S.
Pat. No. 7,153,507), Tysabri.RTM. (Natalizumab,
anti-.alpha.4integrin mAb); Valortim.RTM. (MDX-1303, anti-B.
anthracis Protective Antigen mAb); ABthrax.TM.; Vectibix.RTM.
(Panitumumab); Xolair.RTM. (Omalizumab), ETI211 (anti-MRSA mAb),
IL-1 Trap (the Fc portion of human IgG1 and the extracellular
domains of both IL-1 receptor components (the Type I receptor and
receptor accessory protein)), VEGF Trap (Ig domains of VEGFR1 fused
to IgG1 Fc), Zenapax.RTM. (Daclizumab); Zenapax.RTM. (Daclizumab,
anti-IL-2Ra mAb), Zevalin.RTM. (Ibritumomab tiuxetan), Zetia
(ezetimibe), Atacicept (TACI-Ig), anti-CD80 monoclonal antibody
(mAb) (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3/huFc
fusion protein, soluble BAFF antagonist); CNTO 148 (Golimumab,
anti-TNF.alpha. mAb); HGS-ETR1 (Mapatumumab; human anti-TRAIL
Receptor-1 mAb); HuMax-CD20 (Ocrelizumab, anti-CD20 human mAb);
HuMax-EGFR (zalutumumab); M200 (Volociximab, anti-.alpha.5.beta.1
integrin mAb); MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1
(IMC-18F1); anti-BR3 mAb; anti-C. difficile Toxin A and Toxin B C
mAbs MDX-066 (CDA-1) and MDX-1388); anti-CD22 dsFv-PE38 conjugates
(CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC); anti-CD3 mAb
(NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333
(anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb;
anti-Cripto mAb; anti-CTGF Idiopathic Pulmonary Fibrosis Phase I
Fibrogen (FG-3019); anti-CTLA4 mAb; anti-eotaxin1 mAb (CAT-213);
anti-FGF8 mAb; anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb;
anti-GDF-8 human mAb (MYO-029); anti-GM-CSF Receptor mAb
(CAM-3001); anti-HepC mAb (HuMax HepC); anti-IFN.alpha. mAb
(MEDI-545, MDX-1103); anti-IGF1R mAb; anti-IGF-1R mAb
(HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12/IL23 mAb (CNTO
1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC);
anti-IL5 Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO
95); anti-IP10 Ulcerative Colitis mAb (MDX-1100); anti-LLY
antibody; BMS-66513; anti-Mannose Receptor/hCG.beta. mAb
(MDX-1307); anti-mesothelin dsFv-PE38 conjugate (CAT-5001);
anti-PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFR.alpha. antibody
(IMC-3G3); anti-TGF.beta. mAb (GC-1008); anti-TRAIL Receptor-2
human mAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb;
anti-ZP3 mAb (HuMax-ZP3); NVS Antibody #1; and NVS Antibody #2; a
sclerostin antibody, such as but not limited to romosozumab,
blosozumab, or BPS 804 (Novartis). Also included can be
therapeutics such as rilotumumab, bixalomer, trebananib, ganitumab,
conatumumab, motesanib diphosphate, brodalumab, vidupiprant,
panitumumab, denosumab, romosozumab NPLATE, PROLIA, VECTIBIX or
XGEVA. Additionally, included in the AI can be a monoclonal
antibody (IgG) that binds human Proprotein Convertase
Subtilisin/Kexin Type 9 (PCSK9), e.g. U.S. Pat. No. 8,030,547, U.S.
Ser. No. 13/469,032, WO2008/057457, WO2008/057458, WO2008/057459,
WO2008/063382, WO2008/133647, WO2009/100297, WO2009/100318,
WO2011/037791, WO2011/053759, WO2011/053783, WO2008/125623,
WO2011/072263, WO2009/055783, WO2012/0544438, WO2010/029513,
WO2011/111007, WO2010/077854, WO2012/088313, WO2012/101251,
WO2012/101252, WO2012/101253, WO2012/109530, and WO2001/031007.
[0164] The drug container of the cassette may also be filled for
treatment or be prefilled with antibodies comprising, but not
limited to, those that recognize any one or a combination of
proteins comprising, but not limited to, the above-mentioned
proteins and/or the following antigens: CD2, CD3, CD4, CD8, CD11a,
CD14, CD18, CD20, CD22, CD23, CD25, CD33, CD40, CD44, CD52, CD80
(B7.1), CD86 (B7.2), CD147, IL-1.alpha., IL-1.beta., IL-2, IL-3,
IL-7, IL-4, IL-5, IL-8, IL-10, IL-2 receptor, IL-4 receptor, IL-6
receptor, IL-13 receptor, IL-18 receptor subunits, FGL2,
PDGF-.beta. and analogs thereof (see U.S. Pat. Nos. 5,272,064 and
5,149,792), VEGF, TGF, TGF-.beta.2, TGF-.beta.1, EGF receptor (see
U.S. Pat. No. 6,235,883) VEGF receptor, hepatocyte growth factor,
osteoprotegerin ligand, interferon gamma, B lymphocyte stimulator
(BlyS, also known as BAFF, THANK, TALL-1, and zTNF4; see Do and
Chen-Kiang (2002), Cytokine Growth Factor Rev. 13(1): 19-25), C5
complement, IgE, tumor antigen CA125, tumor antigen MUC1, PEM
antigen, LCG (which is a gene product that is expressed in
association with lung cancer), HER-2, a tumor-associated
glycoprotein TAG-72, the SK-1 antigen, tumor-associated epitopes
that are present in elevated levels in the sera of patients with
colon and/or pancreatic cancer, cancer-associated epitopes or
proteins expressed on breast, colon, squamous cell, prostate,
pancreatic, lung, and/or kidney cancer cells and/or on melanoma,
glioma, or neuroblastoma cells, the necrotic core of a tumor,
integrin alpha 4 beta 7, the integrin VLA-4, B2 integrins, TRAIL
receptors 1, 2, 3, and 4, RANK, RANK ligand, TNF-.alpha., the
adhesion molecule VAP-1, epithelial cell adhesion molecule (EpCAM),
intercellular adhesion molecule-3 (ICAM-3), leukointegrin adhesin,
the platelet glycoprotein gp IIb/IIIa, cardiac myosin heavy chain,
parathyroid hormone, rNAPc2 (which is an inhibitor of factor
Vila-tissue factor), MHC I, carcinoembryonic antigen (CEA),
alpha-fetoprotein (AFP), tumor necrosis factor (TNF), CTLA-4 (which
is a cytotoxic T lymphocyte-associated antigen), Fc-.gamma.-1
receptor, HLA-DR 10 beta, HLA-DR antigen, L-selectin, Respiratory
Syncitial Virus, human immunodeficiency virus (HIV), hepatitis B
virus (HBV), Streptococcus mutans, and Staphylococcus aureus.
[0165] Additional examples of known antibodies that may be
contained in the drug container of the cassette can comprise but
are not limited to adalimumab, bevacizumab, infliximab, abciximab,
alemtuzumab, bapineuzumab, basiliximab, belimumab, briakinumab,
canakinumab, certolizumab pegol, cetuximab, conatumumab, denosumab,
eculizumab, gemtuzumab ozogamicin, golimumab, ibritumomab tiuxetan,
labetuzumab, mapatumumab, matuzumab, mepolizumab, motavizumab,
muromonab-CD3, natalizumab, nimotuzumab, ofatumumab, omalizumab,
oregovomab, palivizumab, panitumumab, pemtumomab, pertuzumab,
ranibizumab, rituximab, rovelizumab, tocilizumab, tositumomab,
trastuzumab, ustekinumab, zalutumumab, and zanolimumab.
[0166] Although the autoinjector system, cassette, and
autoinjector, have been described in terms of exemplary
embodiments, it is not limited thereto. Rather, the appended claims
should be construed broadly, to comprise other variants and
embodiments of same, which may be made by those skilled in the art
without departing from the scope and range of equivalents of the
autoinjector system, cassette, and autoinjector and their
elements.
* * * * *