U.S. patent application number 15/690612 was filed with the patent office on 2017-12-21 for lock out member with different cross sections.
The applicant listed for this patent is SANOFI-AVENTIS DEUTSCHLAND GMBH. Invention is credited to Christian Nessel.
Application Number | 20170361035 15/690612 |
Document ID | / |
Family ID | 44513308 |
Filed Date | 2017-12-21 |
United States Patent
Application |
20170361035 |
Kind Code |
A1 |
Nessel; Christian |
December 21, 2017 |
LOCK OUT MEMBER WITH DIFFERENT CROSS SECTIONS
Abstract
An apparatus is presented comprising a lock out member
configured to be implemented into a medical device, in particular a
dispense interface, attachable to a second medical device, in
particular a main body, wherein said lock out member is configured
to prevent a second attachment of said medical device to said
second medical device, wherein said lock out member has at least a
first area with a first cross-sectional area, wherein said lock out
member has at least a second area having a second cross-sectional
area smaller than the first cross-sectional area, such that an
electric resistance is defined between opposite ends of the lockout
member and wherein said lock out member, at least in the second
area, is made of a conductive material.
Inventors: |
Nessel; Christian;
(Frankfurt am Main, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI-AVENTIS DEUTSCHLAND GMBH |
Frankfurt Am Main |
|
DE |
|
|
Family ID: |
44513308 |
Appl. No.: |
15/690612 |
Filed: |
August 30, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14113861 |
Oct 25, 2013 |
9770562 |
|
|
PCT/EP12/58258 |
May 4, 2012 |
|
|
|
15690612 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/50 20130101; A61M
2205/27 20130101; A61M 5/19 20130101; A61M 5/20 20130101; G01R
27/02 20130101; A61M 5/2066 20130101; A61M 5/5086 20130101; A61M
5/3294 20130101 |
International
Class: |
A61M 5/50 20060101
A61M005/50; A61M 5/19 20060101 A61M005/19; A61M 5/20 20060101
A61M005/20; G01R 27/02 20060101 G01R027/02; A61M 5/32 20060101
A61M005/32 |
Foreign Application Data
Date |
Code |
Application Number |
May 6, 2011 |
EP |
11165120.4 |
Claims
1. An apparatus, comprising: a lock out member configured to be
implemented into a medical device, the proximal end of the medical
device attachable to the distal end of a second medical device,
wherein said lock out member has at least one first area with a
first cross-sectional area and wherein said lock out member has at
least one second area having a second cross-sectional area smaller
than the first cross-sectional area, such that an electric
resistance is defined between opposite ends of the lockout member,
and wherein said lock out member, at least in the at least one
second area, is made of a conductive material, and wherein each of
the at least one second area comprises one or more cut-outs or
perforations.
2. The apparatus according to claim 1, wherein said apparatus
further comprises means configured to be conductively attached to a
device, capable of measuring the resistance of at least said second
area of said lock out spring.
3. The apparatus according to claim 1, wherein the second medical
device refers to a main body.
4. The apparatus according to claim 1, wherein the medical device
refers to a dispense interface.
5. The apparatus according to claim 1, wherein said second
cross-sectional area is at most 30% of said first-cross sectional
area.
6. The apparatus according to claim 5, wherein said second
cross-sectional area is 20% of said first-cross sectional area.
7. The apparatus according to claim 5, wherein said second
cross-sectional area is 10% of said first-cross sectional area.
8. The apparatus according to claim 1, wherein said lock out spring
is substantially made of metal.
9. The apparatus according to claim 1, wherein said conductive
material comprises a Negative Temperature Coefficient Thermistor or
a Positive Temperature Coefficient Thermistor.
10. The apparatus according to claim 1, wherein said lock out
spring is configured to be implemented into said medical device by
form fit, force fit and/or material bonding.
11. The apparatus according to claim 1, wherein said lock out
spring is configured to be implemented close to at least one
cartridge containing a liquid of said medical device.
12. The apparatus according to claim 1, wherein said lock out
spring is configured to be implemented in contact with at least one
cartridge containing a liquid of said medical device.
13. The apparatus according to claim 1, wherein said lock out
spring is configured to be implemented into a dispense
interface.
14. A method for connecting an apparatus for drug delivery
comprising the steps of measuring the electric resistance of at
least a second area of a lock out spring of an apparatus as claimed
in claim 1, and determining said electric resistance of at least
said second area of said lock out spring.
15. The method according to claim 14, wherein a temperature is
determined based at least in part on the determined resistance.
16. The method according to claim 14, wherein the resistance is
measured using a direct or indirect method.
17. The method according to claim 14, wherein the resistance is
measured before a medical device, to which an element is attached,
is used.
18. The method according to claim 15, wherein a user is informed or
the use of said medical device is prohibited, if the measured
temperature is and/or was outside of a predefined interval.
19. The method according to claim 14, wherein the determined
resistance is used to identify the lock out spring.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 14/113,861, filed Oct. 25, 2013, which is a
U.S. National Phase Application pursuant to 35 U.S.C. .sctn.371 of
International Application No. PCT/EP2012/058258 filed May 4, 2012,
which claims priority to European Patent Application No. 11165120.4
filed May 6, 2011. The entire disclosure contents of these
applications are herewith incorporated by reference into the
present application.
FIELD OF DISCLOSURE
[0002] The present patent application relates to medical devices of
delivering at least two drug agents from separate reservoirs. Such
drug agents may comprise a first and a second medicament. The
medical device includes a dose setting mechanism for delivering the
drug automatically or manually by the user.
[0003] The drug agents may be contained in two or more multiple
dose reservoirs, containers or packages, each containing
independent (single drug compound) or pre-mixed (co-formulated
multiple drug compounds) drug agents.
BACKGROUND
[0004] Certain disease states require treatment using one or more
different medicaments. Some drug compounds need to be delivered in
a specific relationship with each other in order to deliver the
optimum therapeutic dose. The present patent application is of
particular benefit where combination therapy is desirable, but not
possible in a single formulation for reasons such as, but not
limited to, stability, compromised therapeutic performance and
toxicology.
[0005] For example, in some cases it might be beneficial to treat a
diabetic with a long acting insulin (also may be referred to as the
first or primary medicament) along with a glucagon-like peptide-1
such as GLP-1 or GLP-1 analog (also may be referred to as the
second drug or secondary medicament).
[0006] Accordingly, there exists a need to provide devices for the
delivery of two or more medicaments in a single injection or
delivery step that is simple for the user to perform without
complicated physical manipulations of the drug delivery device. The
proposed drug delivery device provides separate storage containers
or cartridge retainers for two or more active drug agents. These
active drug agents are then only combined and/or delivered to the
patient during a single delivery procedure. These active agents may
be administered together in a combined dose or alternatively, these
active agents may be combined in a sequential manner, one after the
other.
SUMMARY
[0007] The drug delivery device also allows for the opportunity of
varying the quantity of the medicaments. For example, one fluid
quantity can be varied by changing the properties of the injection
device (e.g., setting a user variable dose or changing the device's
"fixed" dose). The second medicament quantity can be changed by
manufacturing a variety of secondary drug containing packages with
each variant containing a different volume and/or concentration of
the second active agent.
[0008] The drug delivery device may have a single dispense
interface. This interface may be configured for fluid communication
with the primary reservoir and with a secondary reservoir of
medicament containing at least one drug agent. The drug dispense
interface can be a type of outlet that allows the two or more
medicaments to exit the system and be delivered to the patient.
[0009] The combination of compounds as discrete units or as a mixed
unit can be delivered to the body via a double-ended needle
assembly. This would provide a combination drug injection system
that, from a user's perspective, would be achieved in a manner that
closely matches the currently available injection devices that use
standard needle assemblies. One possible delivery procedure may
involve the following steps: [0010] 1. Attach a dispense interface
to a distal end of the electro-mechanical injection device. The
dispense interface comprises a first and a second proximal needle.
The first and second needles pierce a first reservoir containing a
primary compound and a second reservoir containing a secondary
compound, respectively. [0011] 2. Attach a dose dispenser, such as
a double-ended needle assembly, to a distal end of the dispense
interface. In this manner, a proximal end of the needle assembly is
in fluidic communication with both the primary compound and
secondary compound. [0012] 3. Dial up/set a desired dose of the
primary compound from the injection device, for example, via a
graphical user interface (GUI). [0013] 4. After the user sets the
dose of the primary compound, the micro-processor controlled
control unit may determine or compute a dose of the secondary
compound and preferably may determine or compute this second dose
based on a previously stored therapeutic dose profile. It is this
computed combination of medicaments that will then be injected by
the user. The therapeutic dose profile may be user selectable.
[0014] 5. Optionally, after the second dose has been computed, the
device may be placed in an armed condition. In such an optional
armed condition, this may be achieved by pressing and/or holding an
"OK" button on a control panel. This condition may provide for
greater than a predefined period of time before the device can be
used to dispense the combined dose. [0015] 6. Then, the user will
insert or apply the distal end of the dose dispenser (e.g., a
double ended needle assembly) into the desired injection site. The
dose of the combination of the primary compound and the secondary
compound (and potentially a third medicament) is administered by
activating an injection user interface (e.g., an injection
button).
[0016] Both medicaments may be delivered via one injection needle
or dose dispenser and in one injection step. This offers a
convenient benefit to the user in terms of reduced user steps
compared to administering two separate injections.
[0017] The dispense interface can also include a lock out
mechanism. Such a lock out mechanism can prevent the dispense
interface from being reattached to the drug delivery device once
the interface has been initially removed from the device. Such a
feature may help reduce the possibility of contamination as well as
prevent possible blunting of the dispense interface needle
injections ends. These features are described in greater detail
below. A lock out mechanism can be implemented via a so called lock
out member, which is activated when the cartridge holder is
attached to the dispense interface. After removing the dispense
interface from the cartridge holder the lock out member prohibits a
further use of the dispense interface.
[0018] Apart from expiring because of possible dates of expiry, the
quality or effectiveness of medicaments may also be affected by
influences of the environment, which can not be foretold.
[0019] Thus the invention faces the technical problem of further
improving the safety and ensuring the quality of medicaments
ejected from medical devices in an economic way without the need of
additional space in the medical device.
[0020] This technical problem is solved by an apparatus, comprising
a lock out member configured to be implemented into a medical
device, in particular a dispense interface, attachable to a second
medical device, in particular a main body, wherein said lock out
member is configured to prevent a second attachment of said medical
device to said second medical device, wherein said lock out member
has at least a first area with a first cross-sectional area,
wherein said lock out member has at least a second area having a
second cross-sectional area smaller than the first cross-sectional
area, such that an electric resistance is defined between opposite
ends of the lockout member and wherein said lock out member, at
least in the at least one second area, is made of a conductive
material.
[0021] This way an already implemented part in the medical device
can be used for the improvement of the safety and the possible
assurance of the quality of medicaments ejected from medical
devices. For example, by measuring the resistance between the
opposite ends of the lockout member, the temperature can be
determined on the basis of the measured resistance. This way, it is
possible to get information about the temperature by measuring the
resistance of the lock out member. To be able to measure a
significant difference in the resistance of the lock out member, it
is necessary, that the resistance changes measurably while the
temperature goes below or above a safe temperature interval for a
medicament. Such a safe temperature interval may be from 0 to
25.degree. C.
[0022] By measuring the resistance, it is also possible to identify
the lock out member. For example, it may be determined whether a
correct lock out member, which can be situated in a dispense
interface, is connected by determining whether the resistance of
the lockout member is within a certain range of values.
[0023] The measuring of the resistance can be performed in various
ways. A direct or an alternating current can be used for this. The
resistance can be measured in a direct method, for example. But it
is as well possible to measure the resistance with an indirect
method. As an indirect method one can use an RC-Oscillator, whereas
the resistance between the opposite ends of the lockout member
provides the at least a part of the resistance for the RC
oscillator. The direct measurement of the resistance can be
replaced by the measurement of a frequency of the RC
oscillator.
[0024] By determining the temperature from the resistance between
the opposite ends of the lockout member at lest a part of the
lockout member can this way be used as a resistance thermometer. A
resistance thermometer is understood as any sort of substantially
conductive material, the resistance of which changes significantly
enough with temperature to be measured.
[0025] The first areas are preferably the whole lock out member
without the at least one second area. All the first areas have
preferably a larger cross-sectional area than the second areas. By
providing at least a second area having a reduced cross-sectional
area, the influence of this area is dominating the overall
resistance of the lock out member. The reduced cross section must
be that small, that a resistance change can be measured in the
relevant temperature ranges. Preferably there are two second areas
with a smaller cross-sectional area compared to the at least one
first area. These two second areas might be shaped identically.
[0026] Here a lock out member is understood as any member, which is
able to prevent a second use of a medical device, in which the lock
out member is implemented, after the medical device, such as a
dispense interface, is detached from a second device, such as a
main body for example. A lock out member can in particular be a
lock out spring. This can be any type of elastic object, which can
store mechanical energy. Such springs can be design as coils
spring, flat springs, cantilever springs or springs with an even
more complex design.
[0027] In a preferred embodiment the apparatus further comprises
means configured to be conductively attached to a device, capable
of measuring the resistance of at least said second area of said
lock out member. Such means could be any kind of connection
interface comprising a conductive material, like simple
projections, which conductively attach to a connected main body.
The main body may comprise a micro-processor control unit, which
can then measure the resistance of the lock out member by well know
means in the state of the art. A conductive connection, for example
by wires, between the lock out member and the micro-processor
control unit can be established for this purpose by means well
known in the art.
[0028] A medical device may further comprise an electronic circuit
for measuring the resistance of the lock out member, for example by
contacts that contact the lockout member.
[0029] It is further preferred, when said second cross section is
at most 30%, in particular at most 20%, preferably at most 10%, of
said first cross section. This way a resistance thermometer can be
easily provided by a significant reduction in the second area of
the lock out member. Surprisingly the functionality of the lock out
mechanism is not negatively influenced by the reduction of the
cross-sectional area of the second area.
[0030] The reduction of the surface can be easily provided by cut
outs of the lock out member. This might be one large cut out, or
preferably multiple small cut outs in form of holes. Those cut outs
are preferably provided in the area of substantially stress-free or
non-bent parts of the lock out member. This way the stability of
the lock out member is not significantly reduced.
[0031] In a preferred embodiment the lock out member is
substantially made of metal. This way the functionality of the
spring is easily provided and at the same time the first and second
areas are conductive and a resistance measurement can be easily
performed. Moreover the equalisation of the temperatures of the
second areas and the medicaments can be improved.
[0032] Not only the resistance measurement of the second areas can
be done by a micro-processor control unit, which can then measure
the resistance of the lock out member by well know means in the
state of the art. But also the determination of a temperature value
according to the measured resistance can be done by the
micro-processor control unit implemented in the main body of the
medical device. This way no further devices for the measurement are
needed.
[0033] The conductive material of the at least one second area can
either comprise a Negative Temperature Coefficient Thermistor or a
Positive Temperature Coefficient Thermistor. The resistance of a
Negative Temperature Coefficient Thermistor decreases with
increasing temperature, while the resistance of a Positive
Temperature Coefficient Thermistor increases with increasing
temperature. Such thermistors use for example semi-conductive metal
oxides or silicon. This way a temperature range of about -100 to
over 100.degree. C. can easily be measureable by the resistance
measurement. The dependence of the resistance is stronger than that
of standard metals.
[0034] According to another embodiment said lock out member is
configured to be implemented into said medical device by form fit,
force fit and/or material bonding. This may be realised by snap
locks, threads, glue or similar connection arrangements.
[0035] By implementing said lock out member into a housing made of
a nonconductive material, such as plastic, it can be easily
guaranteed to measure the resistance of the lock out member only,
without influencing the resistance measurement by further
resistances in contact with the lock out member.
[0036] It is further preferred, when said lock out member is
configured to be implemented close to at least one cartridge
containing a liquid of said medical device. Since the temperature
of the liquid is actually of interest, a reasonable value of the
temperature of the liquid can be easily determined by positioning
the lock out member close to the liquid or to the cartridges
containing the liquid respectively.
[0037] In a further embodiment said lock out member is configured
to be implemented in contact with at least one cartridge containing
a liquid of said medical device. By designing and positioning the
lock out member in such a way that at least one cartridge can be in
contact with the lock out member, while the main body containing
the cartridge is attached to the medical device containing the lock
out member, a further improvement of the estimation of the actual
temperature of the liquid can be made.
[0038] Preferably said lock out member is configured to be
implemented into a dispense interface. No modifications of the main
body, for example, need to be done. The dispense interface provides
an easy solution to use its lock out member to measure the
temperature. It is possible to design the medical device in such a
way, that the dispense interface must be attached to the main body
in order to use the medical device. This way it can be assured to
be able to measure the temperature, when the medical device is
about to be used.
[0039] The technical problem is further solved by a method
comprising the steps of measuring the electric resistance of at
least a second area of a lock out member, wherein said lock out
member has at least a first area with a first cross-sectional area,
wherein said second area has a second cross-sectional area smaller
than the first cross-sectional area and wherein said lock out
member, at least in the second area, is made of a conductive
material and determining said electric resistance of at least said
second area of said lock out member.
[0040] This way an easy to implement method is provided, without
the use of any additional devices, such as thermometers, and
nevertheless being able to for example measure the temperature or
detect the type of the lockout member, thus improving the assurance
that the temperature did not go below or above a temperature
interval, which would deteriorate the quality of medicaments, or
that the correct devices (for example dispense interface with
lockout member and medical device) are attached.
[0041] According to a further embodiment of the method a
temperature is determined based at least in part on the determined
resistance. By determining the temperature, the assurance that the
temperature did not go below or above a temperature interval is
improved, which would otherwise deteriorate the quality of
medicaments.
[0042] According to a further embodiment of the method the
resistance is measured at predefined points in times. This way, a
power consuming resistance measurement does not need to be done
constantly. Those predefined points in time to perform a resistance
and thus a temperature measurement, might be saved in the
micro-processor control unit or might also be editable by a
user.
[0043] Preferably the resistance is measured using a direct or
indirect method. Direct or alternating current can be used for
this. A sufficient and easy measurement of the resistance can be
performed by using a direct current provided by an internal
battery, for example. The resistance can be measured in a direct
method known from the state of the art, for example. But it is as
well possible to measure the resistance with an indirect method. As
an indirect method one can use an RC-Oscillator, whereas the
resistance between the opposite ends of the lockout member provides
the at least a part of the resistance for the RC oscillator. The
direct measurement of the resistance can be replaced by the
measurement of a frequency of the RC oscillator.
[0044] In a further embodiment of the method the resistance is
measured before a medical device, to which the lock out member is
attached, is used. A resistance and thus temperature measurement
only need to be done, when the medical device is actually used. The
power consumption can this way be further reduced. In case the
temperature is outside of a predefined temperature interval, the
user can be informed, for example.
[0045] The user can further be informed or the use of said medical
device can be prohibited, if the measured temperature is and/or was
outside of a predefined temperature interval. By doing so, the
safety can be further improved. In case the temperature was once
outside a predefined allowed temperature interval, the use of the
medical device and thus the ejection of a medicament can be
completely prevented, for example.
[0046] If the determined resistance is used to identify the lock
out member, the assurance that the correct devices are attached to
each other can be improved. The lock out member can be implemented
in a dispense interface, for example, and before it can be used by
a user, it can be checked whether the dispense interface is
compatible with or allowed to be used with the medical device, to
which the dispense interface is attached.
BRIEF DESCRIPTION OF THE FIGURES
[0047] These as well as other advantages of various aspects of the
present invention will become apparent to those of ordinary skill
in the art by reading the following detailed description, with
appropriate reference to the accompanying drawings, in which:
[0048] FIG. 1 illustrates a perspective view of the delivery device
illustrated in FIGS. 1a and 1b with an end cap of the device
removed;
[0049] FIG. 2 illustrates a perspective view of the delivery device
distal end showing the cartridge;
[0050] FIG. 3 illustrates a perspective view of the cartridge
holder illustrated in FIG. 1 with one cartridge retainer in an open
position;
[0051] FIG. 4 illustrates a dispense interface and a dose dispenser
that may be removably mounted on a distal end of the delivery
device illustrated in FIG. 1;
[0052] FIG. 5 illustrates the dispense interface and the dose
dispenser illustrated in FIG. 4 mounted on a distal end of the
delivery device illustrated in FIG. 1;
[0053] FIG. 6 illustrates one arrangement of the dose dispenser
that may be mounted on a distal end of the delivery device;
[0054] FIG. 7 illustrates a perspective view of the dispense
interface illustrated in FIG. 4;
[0055] FIG. 8 illustrates another perspective view of the dispense
interface illustrated in FIG. 4;
[0056] FIG. 9 illustrates a cross-sectional view of the dispense
interface illustrated in FIG. 4;
[0057] FIG. 10 illustrates an exploded view of the dispense
interface illustrated in FIG. 4;
[0058] FIG. 11 illustrates a cross-sectional view of the dispense
interface and dose dispenser mounted onto a drug delivery device,
such as the device illustrated in FIG. 1;
[0059] FIG. 12 illustrates a cross sectional view of another
dispense interface with a lock out member;
[0060] FIG. 13 illustrates a perspective view of a lock out member
of the dispense interface illustrated in FIG. 12;
[0061] FIG. 14 illustrates a cross-sectional view of the dispense
interface of FIG. 12 mounted on a drug delivery device along with a
dose dispenser attached to the dispense interface.
[0062] FIG. 15a illustrates a perspective view of a an embodiment
of a lock out member according to the invention
[0063] FIG. 15b illustrates a perspective view of a further
embodiment of a lock out member according to the invention
[0064] FIG. 15c illustrates a perspective view of a further
embodiment of a lock out member according to the invention
DETAILED DESCRIPTION
[0065] The drug delivery device illustrated in FIG. 1 comprises a
main body 14 that extends from a proximal end 16 to a distal end
15. At the distal end 15, a removable end cap or cover 18 is
provided. This end cap 18 and the distal end 15 of the main body 14
work together to provide a snap fit or form fit connection so that
once the cover 18 is slid onto the distal end 15 of the main body
14, this frictional fit between the cap and the main body outer
surface 20 prevents the cover from inadvertently falling off the
main body.
[0066] The main body 14 contains a micro-processor control unit, an
electro-mechanical drive train, and at least two medicament
reservoirs. When the end cap or cover 18 is removed from the device
10 (as illustrated in FIG. 1), a dispense interface 200 is mounted
to the distal end 15 of the main body 14, and a dose dispenser
(e.g., a needle assembly) is attached to the interface. The drug
delivery device 10 can be used to administer a computed dose of a
second medicament (secondary drug compound) and a variable dose of
a first medicament (primary drug compound) through a single needle
assembly, such as a double ended needle assembly.
[0067] A control panel region 60 is provided near the proximal end
of the main body 14. Preferably, this control panel region 60
comprises a digital display 80 along with a plurality of human
interface elements that can be manipulated by a user to set and
inject a combined dose. In this arrangement, the control panel
region comprises a first dose setting button 62, a second dose
setting button 64 and a third button 66 designated with the symbol
"OK." In addition, along the most proximal end of the main body, an
injection button 74 is also provided (not visible in the
perspective view of FIG. 1).
[0068] The cartridge holder 40 can be removably attached to the
main body 14 and may contain at least two cartridge retainers 50
and 52. Each retainer is configured so as to contain one medicament
reservoir, such as a glass cartridge. Preferably, each cartridge
contains a different medicament.
[0069] In addition, at the distal end of the cartridge holder 40,
the drug delivery device illustrated in FIG. 1 includes a dispense
interface 200. As will be described in relation to FIG. 4, in one
arrangement, this dispense interface 200 includes a main outer body
212 that is removably attached to a distal end 42 of the cartridge
housing 40. As can be seen in FIG. 1, a distal end 214 of the
dispense interface 200 preferably comprises a needle hub 216. This
needle hub 216 may be configured so as to allow a dose dispenser,
such as a conventional pen type injection needle assembly, to be
removably mounted to the drug delivery device 10.
[0070] Once the device is turned on, the digital display 80 shown
in FIG. 1 illuminates and provides the user certain device
information, preferably information relating to the medicaments
contained within the cartridge holder 40. For example, the user is
provided with certain information relating to both the primary
medicament (Drug A) and the secondary medicament (Drug B).
[0071] As shown in FIG. 3, the first and a second cartridge
retainers 50, 52 comprise hinged cartridge retainers. These hinged
retainers allow user access to the cartridges. FIG. 3 illustrates a
perspective view of the cartridge holder 40 illustrated in FIG. 1
with the first hinged cartridge retainer 50 in an open position.
FIG. 3 illustrates how a user might access the first cartridge 90
by opening up the first retainer 50 and thereby having access to
the first cartridge 90.
[0072] As mentioned above when discussing FIG. 1, a dispense
interface 200 is coupled to the distal end of the cartridge holder
40. FIG. 4 illustrates a flat view of the dispense interface 200
unconnected to the distal end of the cartridge holder 40. A dose
dispenser or needle assembly that may be used with the interface
200 is also illustrated and is provided in a protective outer cap
420.
[0073] In FIG. 5, the dispense interface 200 illustrated in FIG. 4
is shown coupled to the cartridge holder 40. The axial attachment
means between the dispense interface 200 and the cartridge holder
40 can be any known axial attachment means to those skilled in the
art, including snap locks, snap fits, snap rings, keyed slots, and
combinations of such connections. The connection or attachment
between the dispense interface and the cartridge holder may also
contain additional features (not shown), such as connectors, stops,
splines, ribs, grooves, pips, clips and the like design features,
that ensure that specific hubs are attachable only to matching drug
delivery devices. Such additional features would prevent the
insertion of a non-appropriate secondary cartridge to a
non-matching injection device.
[0074] FIG. 5 also illustrates the needle assembly 400 and
protective cover 420 coupled to the distal end of the dispense
interface 200 that may be screwed onto the needle hub of the
interface 200. FIG. 6 illustrates a cross sectional view of the
double ended needle assembly 402 mounted on the dispense interface
200 in FIG. 5.
[0075] The needle assembly 400 illustrated in FIG. 6 comprises a
double ended needle 406 and a hub 401. The double ended needle or
cannula 406 is fixedly mounted in a needle hub 401. This needle hub
401 comprises a circular disk shaped element which has along its
periphery a circumferential depending sleeve 403. Along an inner
wall of this hub member 401, a thread 404 is provided. This thread
404 allows the needle hub 401 to be screwed onto the dispense
interface 200 which, in one preferred arrangement, is provided with
a corresponding outer thread along a distal hub. At a center
portion of the hub element 401 there is provided a protrusion 402.
This protrusion 402 projects from the hub in an opposite direction
of the sleeve member. A double ended needle 406 is mounted
centrally through the protrusion 402 and the needle hub 401. This
double ended needle 406 is mounted such that a first or distal
piercing end 405 of the double ended needle forms an injecting part
for piercing an injection site (e.g., the skin of a user).
[0076] Similarly, a second or proximal piercing end 406 of the
needle assembly 400 protrudes from an opposite side of the circular
disc so that it is concentrically surrounded by the sleeve 403. In
one needle assembly arrangement, the second or proximal piercing
end 406 may be shorter than the sleeve 403 so that this sleeve to
some extent protects the pointed end of the back sleeve. The needle
cover cap 420 illustrated in FIGS. 11 and 12 provides a form fit
around the outer surface 403 of the hub 401.
[0077] Referring now to FIG. 4-11, one preferred arrangement of
this interface 200 will now be discussed. In this one preferred
arrangement, this interface 200 comprises: [0078] a. a main outer
body 210, [0079] b. an first inner body 220, [0080] c. a second
inner body 230, [0081] d. a first piercing needle 240, [0082] e. a
second piercing needle 250, [0083] f. a valve seal 260, and [0084]
g. a septum 270.
[0085] The main outer body 210 comprises a main body proximal end
212 and a main body distal end 214. At the proximal end 212 of the
outer body 210, a connecting member is configured so as to allow
the dispense interface 200 to be attached to the distal end of the
cartridge holder 40. Preferably, the connecting member is
configured so as to allow the dispense interface 200 to be
removably connected the cartridge holder 40. In one preferred
interface arrangement, the proximal end of the interface 200 is
configured with an upwardly extending wall 218 having at least one
recess. For example, as may be seen from FIG. 8, the upwardly
extending wall 218 comprises at least a first recess 217 and a
second recess 219.
[0086] Preferably, the first and the second recesses 217, 219 are
positioned within this main outer body wall so as to cooperate with
an outwardly protruding member located near the distal end of the
cartridge housing 40 of the drug delivery device 10. For example,
this outwardly protruding member 48 of the cartridge housing may be
seen in FIGS. 4 and 5. A second similar protruding member is
provided on the opposite side of the cartridge housing. As such,
when the interface 200 is axially slid over the distal end of the
cartridge housing 40, the outwardly protruding members will
cooperate with the first and second recess 217, 219 to form an
interference fit, form fit, or snap lock. Alternatively, and as
those of skill in the art will recognize, any other similar
connection mechanism that allows for the dispense interface and the
cartridge housing 40 to be axially coupled could be used as
well.
[0087] The main outer body 210 and the distal end of the cartridge
holder 40 act to form an axially engaging snap lock or snap fit
arrangement that could be axially slid onto the distal end of the
cartridge housing. In one alternative arrangement, the dispense
interface 200 may be provided with a coding feature so as to
prevent inadvertent dispense interface cross use. That is, the
inner body of the hub could be geometrically configured so as to
prevent an inadvertent cross use of one or more dispense
interfaces.
[0088] A mounting hub is provided at a distal end of the main outer
body 210 of the dispense interface 200. Such a mounting hub can be
configured to be releasably connected to a needle assembly. As just
one example, this connecting means 216 may comprise an outer thread
that engages an inner thread provided along an inner wall surface
of a needle hub of a needle assembly, such as the needle assembly
400 illustrated in FIG. 6. Alternative releasable connectors may
also be provided such as a snap lock, a snap lock released through
threads, a bayonet lock, a form fit, or other similar connection
arrangements.
[0089] The dispense interface 200 further comprises a first inner
body 220. Certain details of this inner body are illustrated in
FIG. 8-11. Preferably, this first inner body 220 is coupled to an
inner surface 215 of the extending wall 218 of the main outer body
210. More preferably, this first inner body 220 is coupled by way
of a rib and groove form fit arrangement to an inner surface of the
outer body 210. For example, as can be seen from FIG. 9, the
extending wall 218 of the main outer body 210 is provided with a
first rib 213a and a second rib 213b. This first rib 213a is also
illustrated in FIG. 10. These ribs 213a and 213b are positioned
along the inner surface 215 of the wall 218 of the outer body 210
and create a form fit or snap lock engagement with cooperating
grooves 224a and 224b of the first inner body 220. In a preferred
arrangement, these cooperating grooves 224a and 224b are provided
along an outer surface 222 of the first inner body 220.
[0090] In addition, as can be seen in FIG. 8-10, a proximal surface
226 near the proximal end of the first inner body 220 may be
configured with at least a first proximally positioned piercing
needle 240 comprising a proximal piercing end portion 244.
Similarly, the first inner body 220 is configured with a second
proximally positioned piercing needle 250 comprising a proximally
piercing end portion 254. Both the first and second needles 240,
250 are rigidly mounted on the proximal surface 226 of the first
inner body 220.
[0091] Preferably, this dispense interface 200 further comprises a
valve arrangement. Such a valve arrangement could be constructed so
as to prevent cross contamination of the first and second
medicaments contained in the first and second reservoirs,
respectively. A preferred valve arrangement may also be configured
so as to prevent back flow and cross contamination of the first and
second medicaments.
[0092] In one preferred system, dispense interface 200 includes a
valve arrangement in the form of a valve seal 260. Such a valve
seal 260 may be provided within a cavity 231 defined by the second
inner body 230, so as to form a holding chamber 280. Preferably,
cavity 231 resides along an upper surface of the second inner body
230. This valve seal comprises an upper surface that defines both a
first fluid groove 264 and second fluid groove 266. For example,
FIG. 9 illustrates the position of the valve seal 260, seated
between the first inner body 220 and the second inner body 230.
During an injection step, the seal valve 260 helps to prevent the
primary medicament in the first pathway from migrating to the
secondary medicament in the second pathway, while also preventing
the secondary medicament in the second pathway from migrating to
the primary medicament in the first pathway. Preferably, this seal
valve 260 comprises a first non-return valve 262 and a second
non-return valve 268. As such, the first non-return valve 262
prevents fluid transferring along the first fluid pathway 264, for
example a groove in the seal valve 260, from returning back into
this pathway 264. Similarly, the second non-return valve 268
prevents fluid transferring along the second fluid pathway 266 from
returning back into this pathway 266.
[0093] Together, the first and second grooves 264, 266 converge
towards the non-return valves 262 and 268 respectively, to then
provide for an output fluid path or a holding chamber 280. This
holding chamber 280 is defined by an inner chamber defined by a
distal end of the second inner body both the first and the second
non return valves 262, 268 along with a pierceable septum 270. As
illustrated, this pierceable septum 270 is positioned between a
distal end portion of the second inner body 230 and an inner
surface defined by the needle hub of the main outer body 210.
[0094] The holding chamber 280 terminates at an outlet port of the
interface 200. This outlet port 290 is preferably centrally located
in the needle hub of the interface 200 and assists in maintaining
the pierceable seal 270 in a stationary position. As such, when a
double ended needle assembly is attached to the needle hub of the
interface (such as the double ended needle illustrated in FIG. 6),
the output fluid path allows both medicaments to be in fluid
communication with the attached needle assembly.
[0095] The hub interface 200 further comprises a second inner body
230. As can be seen from FIG. 9, this second inner body 230 has an
upper surface that defines a recess, and the valve seal 260 is
positioned within this recess. Therefore, when the interface 200 is
assembled as shown in FIG. 9, the second inner body 230 will be
positioned between a distal end of the outer body 210 and the first
inner body 220. Together, second inner body 230 and the main outer
body hold the septum 270 in place. The distal end of the inner body
230 may also form a cavity or holding chamber that can be
configured to be fluid communication with both the first groove 264
and the second groove 266 of the valve seal.
[0096] Axially sliding the main outer body 210 over the distal end
of the drug delivery device attaches the dispense interface 200 to
the multi-use device. In this manner, a fluid communication may be
created between the first needle 240 and the second needle 250 with
the primary medicament of the first cartridge and the secondary
medicament of the second cartridge, respectively.
[0097] FIG. 11 illustrates the dispense interface 200 after it has
been mounted onto the distal end 42 of the cartridge holder 40 of
the drug delivery device 10 illustrated in FIG. 1. A double ended
needle 400 is also mounted to the distal end of this interface. The
cartridge holder 40 is illustrated as having a first cartridge
containing a first medicament and a second cartridge containing a
second medicament.
[0098] When the interface 200 is first mounted over the distal end
of the cartridge holder 40, the proximal piercing end 244 of the
first piercing needle 240 pierces the septum of the first cartridge
90 and thereby resides in fluid communication with the primary
medicament 92 of the first cartridge 90. A distal end of the first
piercing needle 240 will also be in fluid communication with a
first fluid path groove 264 defined by the valve seal 260.
[0099] Similarly, the proximal piercing end 254 of the second
piercing needle 250 pierces the septum of the second cartridge 100
and thereby resides in fluid communication with the secondary
medicament 102 of the second cartridge 100. A distal end of this
second piercing needle 250 will also be in fluid communication with
a second fluid path groove 266 defined by the valve seal 260.
[0100] FIG. 11 illustrates a preferred arrangement of such a
dispense interface 200 that is coupled to a distal end 15 of the
main body 14 of drug delivery device 10. Preferably, such a
dispense interface 200 is removably coupled to the cartridge holder
40 of the drug delivery device 10.
[0101] As illustrated in FIG. 11, the dispense interface 200 is
coupled to the distal end of a cartridge housing 40. This cartridge
holder 40 is illustrated as containing the first cartridge 90
containing the primary medicament 92 and the second cartridge 100
containing the secondary medicament 102. Once coupled to the
cartridge housing 40, the dispense interface 200 essentially
provides a mechanism for providing a fluid communication path from
the first and second cartridges 90, 100 to the common holding
chamber 280. This holding chamber 280 is illustrated as being in
fluid communication with a dose dispenser. Here, as illustrated,
this dose dispenser comprises the double ended needle assembly 400.
As illustrated, the proximal end of the double ended needle
assembly is in fluid communication with the chamber 280.
[0102] In one preferred arrangement, the dispense interface is
configured so that it attaches to the main body in only one
orientation, that is it is fitted only one way round. As such as
illustrated in FIG. 11, once the dispense interface 200 is attached
to the cartridge holder 40, the primary needle 240 can only be used
for fluid communication with the primary medicament 92 of the first
cartridge 90 and the interface 200 would be prevented from being
reattached to the holder 40 so that the primary needle 240 could
now be used for fluid communication with the secondary medicament
102 of the second cartridge 100. Such a one way around connecting
mechanism may help to reduce potential cross contamination between
the two medicaments 92 and 102.
[0103] FIG. 12 illustrates a cross sectional view of another
dispense interface with a lock out member. As may be seen from FIG.
12, the dispense interface 200 further comprises a dispense
interface lockout member in the form of a lockout spring 2600. FIG.
13 illustrates a perspective view of such one arrangement of such a
lock out member 2600 in an initial, unbiased or unstressed state.
One reason that a lock out member may be incorporated into a
dispense interface, such as the interface 200 illustrated in FIG.
12, is to ensure that once the dispense interface is removed from
the drug delivery device, the dispense interface cannot be
re-attached and used a second time. Preventing re-attachment tends
to ensure that medicament is not allowed to reside in the dispense
interface 200 indefinitely and contaminate the drug delivered to
the patient.
[0104] FIG. 12 illustrates a perspective cross sectional view of
one arrangement of the dispense interface lock out member 2600
illustrated in FIG. 13 seated on the inner body 220 illustrated in
FIG. 12. In this illustrated arrangement, the lock out member
resides in a first or an initial position. As illustrated, the lock
out member 2600 extends from a distal spring end 2604 to a proximal
spring end 2610. Near its distal end 2604, the lock out member 2600
comprises a spring tip 2620. This spring tip 2620 comprises a tab
2622 defining a recess 2624.
[0105] Near its proximal end 2610, the lock out member 2600
comprises a first spring arm 2630 and a second spring arm 2640. For
example, the first spring arm 2630 extends proximally from a first
pivot point 2632 of the spring 2600. Similarly, the second spring
arm 2640 extends proximally from a second pivot point 2642 of the
spring 2600. In the initial spring position illustrated in FIG. 13
and FIG. 12, both the first and the second spring arms 2630, 2640
reside in an unstressed state. That is, both arms flex radially
outward, away from one another a spaced amount defining an initial
distance DM1 2644 of a mouth created between the first and the
second spring arm 2630, 2640. When the spring 2600 is placed within
a stressed state (so as to lock out the spring preventing
re-attachment), the first and second spring arms 2630, 2640 flex
towards one another at the first and second pivot points 2632,
2642, respectively. This flexing causes the arms 2630, 2640 to
reduce the initial distance DM1 of the mouth to a smaller second
mouth distance DM2.
[0106] FIG. 14 illustrates the dispense interface 200 after it has
been mounted onto the distal end 15 of the cartridge holder 40 of
the drug delivery device 10. As illustrated, a double ended needle
assembly 400 is also mounted to the distal end of this interface.
The cartridge holder 40 is illustrated as having a first cartridge
90 containing a first medicament 92 and a second cartridge 100
containing a second medicament 102. As can be seen the lock out
member 2600 is in direct contact with the cartridges 90, 100,
allowing for a better equalisation between the temperature of the
medicaments 102, 92 and the lock out member 2600.
[0107] FIGS. 15a and 15b show a modification of the lock out member
2600 illustrated in FIG. 13. The modifications, which have been
done, compared to the lock out member 2600 illustrated in FIG. 13
are the cut outs in the second areas 300 and 302. By perforating
the lock out member 2600 with holes the cross-sectional area of the
second areas 300 and 302 is reduced, so that the electric
resistance between opposite ends of the lockout member may be
defined at a certain value or level, for example between the spring
arms 2630 and 2640. In an example embodiment, the lock out member
2600 may be used as a resistance thermometer. The resistance
measurement can easily be realised, if the lock out member is made
of metal and by using the spring arms 2630 and 2640 as two contacts
for a resistance measurement. The current has to pass the areas 300
and 302, which have a high resistance compared to the first areas
304, 306, 308, 310 and 312. The second areas 300, 302 therefore
dominate the resistance measurement and can be used as a resistor
with a predefined resistance, or as a resistance thermometer. By
implementing the perforations in a substantially plane part of the
lock out member 2600 the stability of the lock out member 2600 is
not significantly influenced. Different dispense interfaces 20 may
comprise lock out members 2600 with different resistance
values.
[0108] The drug delivery device may comprise an electronic circuit
for measuring the resistance of the lock out member 2600, for
example by contacts that contact the spring arms 2630 and 2640 when
the dispense interface 200 is attached to the device 10. By
measuring the resistance, the lock out member 2600 may be
identified. For example, it may be determined whether a correct
lock out member and/or dispense interface is connected by
determining whether the resistance of the lockout member 2600 is
within a certain range of values.
[0109] By providing two second areas 300, 302 the resistance of
these areas is measured in series in this case. Since the
temperature at the two second areas are very likely the same, this
one temperature can still be determined easily by one skilled in
the art. By providing two second areas 300, 302 the effect of the
temperature on the resistance can be increased in a simple way. By
providing the second areas 300, 302 symmetrically in the lock out
member 2600, the lock out member 2600 is still stressed uniformly
and symmetrically, even with the cut outs.
[0110] Of course, different numbers of cut outs in a second area
and different numbers of second areas may be provided in a lock out
member.
[0111] FIG. 15c shows another embodiment of the second areas 310,
312 in the lock out member 2600. The reduction of the cross section
of the second areas 314, 316 is in this case achieved by two large
cut outs, which are easier to produce than multiple smaller cut
outs.
[0112] Such cut outs might be produced by first manufacturing the
lock out member 2600 as illustrated in FIG. 13 and afterwards laser
processing the second areas 300, 302, 314, 316 and thus producing
the cut outs. The cut outs might also be produced with mechanical
tools, by stamping or punching, for example. Though, the second
areas might also be incorporated into the lock out member 2600
during the manufacture of the lock out member itself.
[0113] The term "drug" or "medicament", as used herein, means a
pharmaceutical formulation containing at least one pharmaceutically
active compound, [0114] wherein in one embodiment the
pharmaceutically active compound has a molecular weight up to 1500
Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a
DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone
or an oligonucleotide, or a mixture of the above-mentioned
pharmaceutically active compound, [0115] wherein in a further
embodiment the pharmaceutically active compound is useful for the
treatment and/or prophylaxis of diabetes mellitus or complications
associated with diabetes mellitus such as diabetic retinopathy,
thromboembolism disorders such as deep vein or pulmonary
thromboembolism, acute coronary syndrome (ACS), angina, myocardial
infarction, cancer, macular degeneration, inflammation, hay fever,
atherosclerosis and/or rheumatoid arthritis, [0116] wherein in a
further embodiment the pharmaceutically active compound comprises
at least one peptide for the treatment and/or prophylaxis of
diabetes mellitus or complications associated with diabetes
mellitus such as diabetic retinopathy, [0117] wherein in a further
embodiment the pharmaceutically active compound comprises at least
one human insulin or a human insulin analogue or derivative,
glucagon-like peptide (GLP-1) or an analogue or derivative thereof,
or exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or
exedin-4.
[0118] Insulin analogues are for example Gly(A21), Arg(B31),
Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28),
Pro(B29) human insulin; Asp(B28) human insulin; human insulin,
wherein proline in position B28 is replaced by Asp, Lys, Leu, Val
or Ala and wherein in position B29 Lys may be replaced by Pro;
Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human
insulin and Des(B30) human insulin.
[0119] Insulin derivates are for example B29-N-myristoyl-des(B30)
human insulin; B29-N-palmitoyl-des(B30) human insulin;
B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin;
B28-N-myristoyl LysB28ProB29 human insulin;
B28-N-palmitoyl-LysB28ProB29 human insulin;
B30-N-myristoyl-ThrB29LysB30 human insulin;
B30-N-palmitoyl-ThrB29LysB30 human insulin;
B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;
B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;
B29-N-(.omega.-carboxyheptadecanoyl)-des(B30) human insulin and
B29-N-(.omega.-carboxyhepta-decanoyl) human insulin.
[0120] Exendin-4 for example means Exendin-4(1-39), a peptide of
the sequence H
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-A-
rg-Leu-Phe-Ile-Glu-Trp-
Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
[0121] Exendin-4 derivatives are for example selected from the
following list of compounds: [0122] H-(Lys)4-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0123] H-(Lys)5-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0124] des Pro36 [Asp28] Exendin-4(1-39),
[0125] des Pro36 [IsoAsp28] Exendin-4(1-39), [0126] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0127] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0128] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0129] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0130] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0131] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39); or [0132] des Pro36 [Asp28] Exendin-4(1-39),
[0133] des Pro36 [IsoAsp28] Exendin-4(1-39), [0134] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0135] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0136] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0137] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0138] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0139] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39), wherein the group -Lys6-NH2 may be bound to the
C-terminus of the Exendin-4 derivative; or an Exendin-4 derivative
of the sequence [0140] H-(Lys)6-des Pro36 [Asp28]
Exendin-4(1-39)-Lys6-NH2, [0141] des Asp28 Pro36, Pro37,
Pro38Exendin-4(1-39)-NH2, [0142] H-(Lys)6-des Pro36, Pro38 [Asp28]
Exendin-4(1-39)-NH2, [0143] H-Asn-(Glu)5des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-NH2, [0144] des Pro36, Pro37, Pro38 [Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0145] H-(Lys)6-des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0146] H-Asn-(Glu)5-des Pro36,
Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0147]
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
[0148] H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]
Exendin-4(1-39)-NH2, [0149] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0150] H-Asn-(Glu)5-des
Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0151]
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0152] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0153]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0154] H-(Lys)6-des Pro36 [Met(O)14,
Asp28] Exendin-4(1-39)-Lys6-NH2, [0155] des Met(O)14 Asp28 Pro36,
Pro37, Pro38 Exendin-4(1-39)-NH2, [0156] H-(Lys)6-desPro36, Pro37,
Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, [0157]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0158] des Pro36, Pro37, Pro38 [Met(O)14,
Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0159] H-(Lys)6-des Pro36,
Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0160]
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0161] H-Lys6-des Pro36 [Met(O)14,
Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, [0162] H-des Asp28
Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
[0163] H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0164] H-Asn-(Glu)5-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0165] des Pro36,
Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0166] H-(Lys)6-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, [0167]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2; or a pharmaceutically acceptable salt
or solvate of any one of the afore-mentioned Exedin-4
derivative.
[0168] Hormones are for example hypophysis hormones or hypothalamus
hormones or regulatory active peptides and their antagonists as
listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine
(Follitropin, Lutropin, Choriongonadotropin, Menotropin),
Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin,
Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
[0169] A polysaccharide is for example a glucosaminoglycane, a
hyaluronic acid, a heparin, a low molecular weight heparin or an
ultra low molecular weight heparin or a derivative thereof, or a
sulphated, e.g. a poly-sulphated form of the above-mentioned
polysaccharides, and/or a pharmaceutically acceptable salt thereof.
An example of a pharmaceutically acceptable salt of a
poly-sulphated low molecular weight heparin is enoxaparin
sodium.
[0170] Antibodies are globular plasma proteins (-150 kDa) that are
also known as immunoglobulins which share a basic structure. As
they have sugar chains added to amino acid residues, they are
glycoproteins. The basic functional unit of each antibody is an
immunoglobulin (Ig) monomer (containing only one Ig unit); secreted
antibodies can also be dimeric with two Ig units as with IgA,
tetrameric with four Ig units like teleost fish IgM, or pentameric
with five Ig units, like mammalian IgM.
[0171] The Ig monomer is a "Y"-shaped molecule that consists of
four polypeptide chains; two identical heavy chains and two
identical light chains connected by disulfide bonds between
cysteine residues. Each heavy chain is about 440 amino acids long;
each light chain is about 220 amino acids long. Heavy and light
chains each contain intrachain disulfide bonds which stabilize
their folding. Each chain is composed of structural domains called
Ig domains. These domains contain about 70-110 amino acids and are
classified into different categories (for example, variable or V,
and constant or C) according to their size and function. They have
a characteristic immunoglobulin fold in which two .beta. sheets
create a "sandwich" shape, held together by interactions between
conserved cysteines and other charged amino acids.
[0172] There are five types of mammalian Ig heavy chain denoted by
.alpha., .delta., .epsilon., .gamma., and .mu.. The type of heavy
chain present defines the isotype of antibody; these chains are
found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
[0173] Distinct heavy chains differ in size and composition;
.alpha. and .gamma. contain approximately 450 amino acids and 6
approximately 500 amino acids, while .mu. and .epsilon. have
approximately 550 amino acids. Each heavy chain has two regions,
the constant region (CH) and the variable region (VH). In one
species, the constant region is essentially identical in all
antibodies of the same isotype, but differs in antibodies of
different isotypes. Heavy chains .gamma., .alpha. and .delta. have
a constant region composed of three tandem Ig domains, and a hinge
region for added flexibility; heavy chains .mu. and .epsilon. have
a constant region composed of four immunoglobulin domains. The
variable region of the heavy chain differs in antibodies produced
by different B cells, but is the same for all antibodies produced
by a single B cell or B cell clone. The variable region of each
heavy chain is approximately 110 amino acids long and is composed
of a single Ig domain.
[0174] In mammals, there are two types of immunoglobulin light
chain denoted by .lamda. and .kappa.. A light chain has two
successive domains: one constant domain (CL) and one variable
domain (VL). The approximate length of a light chain is 211 to 217
amino acids. Each antibody contains two light chains that are
always identical; only one type of light chain, .kappa. or .lamda.,
is present per antibody in mammals.
[0175] Although the general structure of all antibodies is very
similar, the unique property of a given antibody is determined by
the variable (V) regions, as detailed above. More specifically,
variable loops, three each the light (VL) and three on the heavy
(VH) chain, are responsible for binding to the antigen, i.e. for
its antigen specificity. These loops are referred to as the
Complementarity Determining Regions (CDRs). Because CDRs from both
VH and VL domains contribute to the antigen-binding site, it is the
combination of the heavy and the light chains, and not either
alone, that determines the final antigen specificity.
[0176] An "antibody fragment" contains at least one antigen binding
fragment as defined above, and exhibits essentially the same
function and specificity as the complete antibody of which the
fragment is derived from. Limited proteolytic digestion with papain
cleaves the Ig prototype into three fragments. Two identical amino
terminal fragments, each containing one entire L chain and about
half an H chain, are the antigen binding fragments (Fab). The third
fragment, similar in size but containing the carboxyl terminal half
of both heavy chains with their interchain disulfide bond, is the
crystalizable fragment (Fc). The Fc contains carbohydrates,
complement-binding, and FcR-binding sites. Limited pepsin digestion
yields a single F(ab')2 fragment containing both Fab pieces and the
hinge region, including the H-H interchain disulfide bond. F(ab')2
is divalent for antigen binding. The disulfide bond of F(ab')2 may
be cleaved in order to obtain Fab'. Moreover, the variable regions
of the heavy and light chains can be fused together to form a
single chain variable fragment (scFv).
[0177] Pharmaceutically acceptable salts are for example acid
addition salts and basic salts. Acid addition salts are e.g. HCl or
HBr salts. Basic salts are e.g. salts having a cation selected from
alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion
N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other
mean: hydrogen, an optionally substituted C1 C6-alkyl group, an
optionally substituted C2-C6-alkenyl group, an optionally
substituted C6-C10-aryl group, or an optionally substituted
C6-C10-heteroaryl group. Further examples of pharmaceutically
acceptable salts are described in "Remington's Pharmaceutical
Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing
Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of
Pharmaceutical Technology.
[0178] Pharmaceutically acceptable solvates are for example
hydrates.
* * * * *