U.S. patent application number 14/113393 was filed with the patent office on 2014-02-20 for valve arrangement for medical device.
This patent application is currently assigned to SANOFI-AVENTIS DEUTSCHLAND GMBH. The applicant listed for this patent is Simon Lewis Bilton, James Alexander Davies, Ilona Eggert, Christopher Nigel Langley, David Moore, Steven Wimpenny. Invention is credited to Simon Lewis Bilton, James Alexander Davies, Ilona Eggert, Christopher Nigel Langley, David Moore, Steven Wimpenny.
Application Number | 20140052079 14/113393 |
Document ID | / |
Family ID | 44993967 |
Filed Date | 2014-02-20 |
United States Patent
Application |
20140052079 |
Kind Code |
A1 |
Eggert; Ilona ; et
al. |
February 20, 2014 |
VALVE ARRANGEMENT FOR MEDICAL DEVICE
Abstract
The invention faces the technical problem of reducing the
uncertainty over exact doses ejected from a medical device and at
the same time providing a homogeneous, but controlled mixture of at
least two fluids while a simple production should be maintained. A
medical device comprising a first valve, a second valve, a first
pre-valve ullage, a second pre-valve ullage, a post-valve ullage
with a first end and a second end and a needle is presented. The
first pre-valve ullage is connected to the post-valve ullage by the
first valve and the second pre-valve ullage is connected to the
post-valve ullage by the second valve. A first fluid is guidable
from the first pre-valve ullage to the post-valve ullage and a
second fluid is guidable from the second pre-valve ullage to the
post-valve ullage.
Inventors: |
Eggert; Ilona; (Frankfurt am
Main, DE) ; Davies; James Alexander; (Warwickshire,
GB) ; Bilton; Simon Lewis; (Warwickshire, GB)
; Moore; David; (Leicestershire, GB) ; Wimpenny;
Steven; (Warwickshire, GB) ; Langley; Christopher
Nigel; (Warwickshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Eggert; Ilona
Davies; James Alexander
Bilton; Simon Lewis
Moore; David
Wimpenny; Steven
Langley; Christopher Nigel |
Frankfurt am Main
Warwickshire
Warwickshire
Leicestershire
Warwickshire
Warwickshire |
|
DE
GB
GB
GB
GB
GB |
|
|
Assignee: |
SANOFI-AVENTIS DEUTSCHLAND
GMBH
Franfurt am Main
DE
|
Family ID: |
44993967 |
Appl. No.: |
14/113393 |
Filed: |
April 26, 2012 |
PCT Filed: |
April 26, 2012 |
PCT NO: |
PCT/EP12/57682 |
371 Date: |
October 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61480063 |
Apr 28, 2011 |
|
|
|
Current U.S.
Class: |
604/246 |
Current CPC
Class: |
A61M 39/22 20130101;
A61M 5/19 20130101; A61M 5/3134 20130101; A61M 2005/3128 20130101;
A61M 5/24 20130101 |
Class at
Publication: |
604/246 |
International
Class: |
A61M 39/22 20060101
A61M039/22 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 8, 2011 |
EP |
11173269.9 |
Claims
1-12. (canceled)
13. Medical device comprising: a first valve, a second valve, a
first pre-valve ullage, a second pre-valve ullage, a post-valve
ullage with a first end and a second end, and a needle, wherein
said first pre-valve ullage is connected to said post-valve ullage
by said first valve, wherein said second pre-valve ullage is
connected to said post-valve ullage by said second valve, wherein a
first fluid is guidable from the first pre-valve ullage to the
post-valve ullage, wherein a second fluid (102) is guidable from
the second pre-valve ullage to the post-valve ullage, wherein a
first end of said needle is inserted into said post-valve ullage
and wherein said post-valve ullage is designed such that there is a
flow inversion between said post-valve ullage and said needle.
14. Medical device according to claim 13, further comprising a
first reservoir and a second reservoir, wherein said first
reservoir is connected to said first pre-valve ullage and said
second reservoir is connected to said second pre-valve ullage.
15. Medical device according to claim 13, wherein a first end of
said needle is inserted into said post-valve ullage at the second
end of the post-valve ullage.
16. Medical device according to claim 13, wherein said first end of
said needle is substantially in the center of said post-valve
ullage.
17. Medical device according to claim 13, wherein the first fluid
and/or the second fluid enter the post-valve ullage substantially
tangentially.
18. Medical device according to claim 13, wherein said first
pre-valve ullage and said second pre-valve ullage are provided by
an inner body and said first valve and said second valve are
provided by a first elastic part and a second elastic part adjacent
to an outer body of said medical device.
19. Medical device according to claim 13, wherein said post-valve
ullage is configured such that said fluid enters the post-valve
ullage at the second end of said post valve ullage.
20. Medical device according to claim 13, wherein said first valve
and said second valve are provided by valves located at the first
end of the post-valve ullage.
21. Medical device according to claim 13, wherein said first valve
is configured to be controlled by the pressure of said fluid in
said first pre-valve ullage and/or said second valve is configured
to be controlled by the pressure of said fluid in said second
pre-valve ullage.
22. Medical device according to claim 13, wherein the first valve
and/or the second valve is at least in part made from one or more
materials selected from the group of TPE, PTFE, silicone and
EPDM.
23. Medical device according to claim 13, wherein said medical
device is a drug delivery system.
24. Medical device according to claim 13, further comprising a
dispense interface comprising said first valve, said second valve,
said first pre-valve ullage, said second pre-valve ullage and said
post-valve ullage with said first end and said second end.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a U.S. National Phase application
pursuant to 35 U.S.C. .sctn.371 of International Application No.
PCT/EP2012/057682 filed Apr. 26, 2012, which claims priority to
U.S. Provisional Patent Application No. 61/480,063 filed Apr. 28,
2011, and European Patent Application No. 11173269.9 filed Jul. 8,
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
for 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 agents automatically or manually by the user.
[0003] The medical device can be an injector, for example a
hand-held injector, especially a pen-type injector, that is an
injector of the kind that provides for administration by injection
of medicinal products from one or more multidose cartridges. In
particular, the present invention relates to such injectors where a
user may set the dose.
[0004] 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
[0005] 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.
[0006] For example, in some cases it may 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).
[0007] 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
[0008] 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.
[0009] The drug delivery device may have a single dispense
interface. This interface may be configured for fluid communication
with a 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.
[0010] The combination of compounds from separate reservoirs can be
delivered to the body via a double-ended needle assembly. This
provides a combination drug injection system that, from a user's
perspective, achieves drug delivery 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:
[0011] 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.
[0012] 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.
[0013] 3. Dial up/set a desired dose of the primary compound from
the injection device, for example, via a graphical user interface
(GUI).
[0014] 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. Alternatively, the user can dial or set a
desired dose of the secondary compound.
[0015] 5. Optionally, after the second dose has been set, the
device may be placed in an armed condition. The optional armed
condition may be achieved by pressing and/or holding an "OK" or an
"Arm" button on a control panel. The armed condition may be
provided for a predefined period of time during which the device
can be used to dispense the combined dose.
[0016] 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).
[0017] 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.
[0018] Using a single device and especially using a single
injection needle to reduce the normally two injection steps to a
single step generates the problem of an uncontrolled mixture of the
two drug agents used.
[0019] It is always necessary for a successful therapy to deliver
the two different drug agents to the patient in a very particular
dose. Since the two drug agents share a common injection needle the
two different drug agents need to mix at some point in the medical
device, in case the two drug agents are administered in a combined
dose. Due to the comparable big volumes and long paths the drug
agents need to pass between the reservoirs and the injection site
an uncontrollable mixture of the medicaments can often not be
avoided, producing an uncertainty on the exact dose
administered.
[0020] In case the two drug agents are administered in a sequential
manner one after another, there is also an uncertainty over the
exact dose administered, especially the exact dose of the second
drug agent, since the fluidic channels in the drug delivery device
are of course at least partially filled with remainders of the
first drug agents, leading again to an uncontrolled mixing of the
two medicaments.
[0021] The invention faces the technical problem of reducing the
uncertainty over exact doses ejected from a medical device and
reducing the risk of cross-contamination of the two or more
medicaments.
[0022] The technical problem is solved by a medical device
comprising a first valve, a second valve, a first pre-valve ullage,
a second pre-valve ullage, a post-valve ullage with a first end and
a second end and a needle. The first pre-valve ullage is connected
to the post-valve ullage by the first valve and the second
pre-valve ullage is connected to the post-valve ullage by the
second valve. A first fluid is guidable from the first pre-valve
ullage to the post-valve ullage and a second fluid is guidable from
the second pre-valve ullage to the post-valve ullage. A first end
of the needle is inserted into the post-valve ullage and the
post-valve ullage is designed such that there is a flow inversion
between the post-valve ullage and the needle.
[0023] By providing two separate valves for each of the at least
two fluids, the fluids are kept separate in their own pre-valve
ullages. This limits the region, where the different fluids can
mix, to the post-valve ullage. It has been found that this way a
much more precise, controlled and predictable mixture of the
different fluid, in particular drug agents, can be ejected from the
medical device. Of course, the pre-valve ullages do not have a
direct connection to each other apart from their connection to the
common post-valve ullage over the respective valves.
[0024] The two separate valves for each fluid also prevent the
first fluid to be pushed into the second pre-valve ullage or even
further back, for example into a reservoir for the second fluid and
vice versa.
[0025] In case the fluids are ejected from the medical device one
after another, the inventive medical device improves the
uncertainty over exact doses, since the common fluidic passage is
reduced to the post-valve ullage. That means that the amount of the
first fluid remaining in the common fluidic passage is effectively
reduced, thus providing a better control of the second dose.
[0026] The volume of the post-valve ullage though is still
sufficient to provide a region, in which both medicaments can mix
sufficiently, so that a homogeneous mixture of the fluids is
provided in case the fluids are ejected together.
[0027] According to another embodiment the medical device further
comprises a first reservoir and a second reservoir, wherein the
first reservoir is connected to the first pre-valve ullage and the
second reservoir is connected to the second pre-valve ullage. These
reservoirs provide separate storage vessels for the first and
second fluid. This is particularly useful for drug agents, which
must not be stored together or in a ready-made mixture. This way,
the fluids, in particular drug agents, mix in the post-valve ullage
for the first time, right before the mixture is ejected from the
medical device and/or injected at the injection site, for
example.
[0028] The reservoirs are preferably detachably attached to the
respective pre-valve ullages. This connection can in particular be
provided by needles or cannulas, which are preferably made from
metal, for example steel. This accounts for the fact, that the
reservoirs might be exchanged with different frequencies than the
part of the medical device containing said ullages and valves.
[0029] The first and second pre-valve ullages can be in constant
fluid communication with the respective reservoir. The valves
prevent the fluids to enter the post-valve ullage while the medical
device is not used.
[0030] According to another embodiment of the medical device, a
first end of the needle is inserted into the post-valve ullage at
the second end of the post-valve ullage. This provides a simple
possibility to guide either fluid or a mixture of both fluids to an
injection site. No further guiding by complicated fluidic systems
is needed and the overall fluidic system from the reservoir to the
injection site, in particular from the post-valve ullage to the
injection site is minimized. This further reduces unnecessary
volume for the fluids to pass and improves the accuracy of the
doses. The needle is preferably made of metal, in particular steel,
to provide a biocompatible material and to be able to directly
inject the fluids into the skin of a user, for example.
[0031] Such a needle can in particular be a double ended needle,
which can be attached to the medical device, providing an
exchangeable injection needle.
[0032] It is further preferred when the first end of the needle is
substantially in the center of the post-valve ullage. On the one
hand, this reduces the danger of damaging the post valve ullage
with the first end of the needle.
[0033] On the other hand, this provides a flow inversion and thus
further improves the flow efficiency. The fluids enter the
post-valve ullage, for example at its first end or at its second
end, and the fluids exit the post-valve ullage through the needle
in or near the center or at or near an opposite end of the
post-valve ullage. This configuration makes the fluid change
directions and thus provides an excellent mixing of the fluids and
an improved flow-out. This effect is especially distinct, when the
fluids enter the post-valve ullage at its second end, since the
flow directions of the fluids during entering and exiting the
post-valve ullage are anti-parallel.
[0034] According to another embodiment of the medical device, the
first fluid and/or the second fluid enter the post-valve ullage
substantially tangentially. That means, if the post valve ullage
has a substantially cylindrical shape for example, the first fluid
and/or the second fluid enter the post-valve ullage tangentially to
its curved surface area. In this way, a particularly effective
mixing of the fluids can be achieved.
[0035] According to the invention the post-valve ullage is designed
such that there is a flow inversion between the post valve ullage
and the needle. This effect can in particular be achieved by
providing a post-valve ullage, into which the fluids enter at the
second end of the post-valve ullage, while the first end of the
needle is located in or near the center or at or near the first end
of the post-valve ullage. This results in the effect that the
fluids flow into the post-valve ullage substantially from the
second end towards the first end of the post-valve ullage and exit
the post-valve ullage through the first end of the needle flowing
substantially from the first end of the post valve ullage in the
direction of the second end of the post valve ullage. Thus, an
antiparallel upward and downward movement of the fluids provides in
this case the flow inversion and therefore an effective mixing of
the fluids.
[0036] The same effect is achieved in case the fluids enter the
post valve ullage at the first end of the post-valve ullage for
example, since at least a part of the fluids will reach the second
end of the post-valve ullage and the fluids will have to flow
towards the first end of the post-valve ullage to reach the center
of the post-valve ullage and to exit through the first end of the
needle. Thus, a flow inversion is achieved in the post-valve ullage
and a particularly effective mixing of the fluids can be
achieved.
[0037] According to another embodiment of the medical device, it is
advantageous, when the first pre-valve ullage and the second
pre-valve ullage are provided by an inner body and the first valve
and the second valve are provided by a first and a second elastic
part respectively adjacent to an outer body of the medical
device.
[0038] This facilitates the production of the medical device. The
valve is provided between outer and inner body, such that no
stand-alone parts are necessary in this arrangement as for example
for diaphragm valves. The first and second elastic parts seal the
fluidic connection between the respective pre-valve ullages and the
post-valve ullage.
[0039] Preferably, the elastic parts have flexible portions such
that the flexible portions can move freely and the valves are
opened and closed depending on the pressure of the respective
fluids in the pre-valve ullages. If the pressure is high enough in
the first pre-valve ullage, the flexible portion is preferably
pushed out of the way opening the first valve and establishing a
fluid connection between the first pre-valve ullage and the post
valve ullage. The second valve can work in the same way. Though, it
is also possible that the valves are activated automatically by a
mechanical mechanism, for example.
[0040] Preferably the valves are of such design, that the valve is
a one way valve and a backpressure from the post-valve ullage
cannot open the valves.
[0041] Such a so called "sleeve valve" can be easily implemented by
a circular diaphragm valve, for example.
[0042] The elastic part might also be designed integrally with the
outer body of the medical device.
[0043] It is preferred, when the post-valve ullage is configured
such that the fluid enters the post-valve ullage at the second end
of the post valve ullage. The fluid can be guided to the second end
of the post-valve ullage by fluidic channels connecting the
respective valve with the second end of the post-valve ullage. This
way a more homogenous mixing of the fluids can be achieved and an
efficient guiding of the fluids with a minimal length of the
fluidic system, since the fluids do not need to be guided to the
first end of the post-valve ullage again. This further promotes the
reduction of the uncertainty over exact doses ejected, while at the
same time a homogeneous, but controlled mixture is provided.
[0044] According to another embodiment of the Medical device, the
first valve and the second valve are provided by valves located at
the first end of the post-valve ullage. This arrangement provides a
minimal channel length from the pre-valve ullages or the reservoirs
to the post-valve ullage or the injection site. This further
reduces the uncertainty over exact doses ejected from the medical
device and at the same time provides a homogeneous, but controlled
mixture of two fluids.
[0045] The valves can be designed as standard umbrella or diaphragm
valves, but may preferably be designed as so called "beak valves".
Such beak valves are substantially funnel shaped with a
point-shaped opening or an opening in form of a slit. In the closed
state the elastic material adjacent to the opening is pre-stressed
such that the opening is closed. The pressure of the fluid can open
force the elastic material aside, so that the beak valve opens.
[0046] It is especially preferred, when the first valve is
configured to be controlled by the pressure of the fluid in the
first pre-valve ullage and/or the second valve is configured to be
controlled by the pressure of the fluid in the second pre-valve
ullage. This provides a very simple and cost-sensitive
implementation of the valves into the medical device, because no
external control of the valves is necessary, for example by
mechanical actuators or the like.
[0047] It is especially preferred when the first valve and/or the
second valve is at least in part made from one or more materials
selected from the group of TPE, PTFE, silicone and EPDM. These
materials are especially suitable since they show a high
biocompatibility, for example requirements for sterilization, and
at the same time provide a sufficient sealing function between the
pre-valve ullage and the post-valve ullage.
[0048] Valves from thermoplastic elastomers (TPE) are especially
easy to produce since they can be molded and only little or no
compounding is necessary to achieve the desired material
properties.
[0049] Polytetrafluoroethylene (PTFE) shows a very low coefficient
of friction optimizing the fluidic properties of the medical
device. Moreover PTFE is subjected to material creep, which can be
advantageous when used in valves and seals, since the valve or seal
creeps a certain amount and can thus match the corresponding
counter-surface to establish a tight seal.
[0050] Silicone is readily tested in medical appliances and
provides good sealing properties combined with good
biocompatibility.
[0051] Valves made from ethylene propylene diene monomer rubber
(EPDM) provide a high resistivity against humidity and ozone.
Furthermore EPDM has a high chemical stability and a high
elasticity, providing excellent properties for sealing
applications.
[0052] In particular the medical device is a drug delivery system.
Especially for drug delivery systems it is of utmost importance to
reduce the uncertainty over exact doses ejected and at the same
time providing a homogeneous, but controlled mixture of the ejected
fluids.
[0053] It is especially advantageous if the medical device further
comprises a dispense interface comprising the first valve, the
second valve, the first pre-valve ullage, the second pre-valve
ullage and the post-valve ullage with the first end and said second
end. The dispense interface can hence be exchanged or replaced
independently from the rest of the medical device, especially a
cartridge holder, containing the first and second reservoir.
BRIEF DESCRIPTION OF THE FIGURES
[0054] 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:
[0055] FIG. 1 illustrates a perspective view of a delivery device
with an end cap of the device removed;
[0056] FIG. 2 illustrates a perspective view of the delivery device
distal end showing the cartridge;
[0057] FIG. 3 illustrates a perspective view of the delivery device
illustrated in FIG. 1 or 2 with one cartridge retainer in an open
position;
[0058] 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;
[0059] 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;
[0060] FIG. 6 illustrates a needle assembly that may be mounted on
a distal end of the delivery device;
[0061] FIG. 7 illustrates a perspective view of the dispense
interface illustrated in FIG. 4;
[0062] FIG. 8 illustrates another perspective view of the dispense
interface illustrated in FIG. 4;
[0063] FIG. 9 illustrates an exemplary embodiment of the invention
in a cross-sectional view of the dispense interface illustrated in
FIG. 4;
[0064] FIG. 10 illustrates an exploded view of the dispense
interface illustrated in FIG. 4;
[0065] FIG. 11 illustrates a cross-sectional view of the dispense
interface and needle assembly mounted onto a drug delivery device,
such as the device illustrated in FIG. 1;
[0066] FIG. 12 illustrates another exemplary embodiment according
to the invention in a cross sectional view;
[0067] FIG. 13 illustrates another exemplary embodiment according
to the invention in a cross sectional view.
DETAILED DESCRIPTION
[0068] 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.
[0069] 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.
[0070] The drive train may exert a pressure on the bung of each
cartridge, respectively, in order to expel the doses of the first
and second medicaments. For example, a piston rod may push the bung
of a cartridge forward a pre-determined amount for a single dose of
medicament. When the cartridge is empty, the piston rod is
retracted completely inside the main body 14, so that the empty
cartridge can be removed and a new cartridge can be inserted.
[0071] 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).
[0072] 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.
[0073] 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.
[0074] 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).
[0075] As shown in FIG. 3, the first and second cartridge retainers
50, 52 may be 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.
[0076] 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 400 that may be used with the
interface 200 is also illustrated and is provided in a protective
outer cap 420.
[0077] 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.
[0078] 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.
[0079] 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).
[0080] 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. 4 and 5 provides a form fit
around the outer surface 403 of the hub 401.
[0081] Referring now to FIGS. 4 to 11, one preferred arrangement of
this interface 200 will now be discussed. In this one preferred
arrangement, this interface 200 comprises:
[0082] a. a main outer body 210,
[0083] b. an first inner body 220,
[0084] c. a second inner body 230,
[0085] d. a first piercing needle 240,
[0086] e. a second piercing needle 250,
[0087] f. a valve seal 260, and
[0088] g. a septum 270.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] Preferably, this dispense interface 200 further comprises a
valve arrangement. The valve arrangement is constructed so as to
prevent cross contamination of the first and second medicaments
contained in the first and second reservoirs, respectively.
Additionally, the valve arrangement is also configured so as to
prevent back flow and cross contamination of the first and second
medicaments.
[0096] 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 or a first pre-valve ullage 264 and second fluid
groove or a second pre-valve ullage 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, this 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. 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 or first pre-valve
ullage 264, for example a groove in the seal valve 260, from
returning back into this pathway or pre-valve ullage 264.
Similarly, the second non-return valve or second pre-valve ullage
268 prevents fluid transferring along the second fluid pathway or
second pre-valve ullage 266 from returning back into this pathway
or pre-valve ullage 266.
[0097] Together, the first and second grooves or pre-valve ullages
264, 266 converge towards the non-return valves 262 and 268
respectively, to then provide for an output fluid path or a
post-valve ullage in form of a holding chamber 280. This holding
chamber 280 is defined by an inner chamber defined by a distal end
of the second inner body, a first end 281 with both the first and
the second non return valves 262, 268 and a second end 282 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.
[0098] The holding chamber or post-valve ullage 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.
[0099] 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 or
first pre-valve ullage 264 and the second groove or second
pre-valve ullage 266 of the valve seal.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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 or post-valve ullage 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
ullage 280.
[0106] 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.
[0107] In an alternative valve arrangement, the dispense interface
may comprise a valve arrangement comprising a sleeve valve
arrangement. For example, FIG. 12 illustrates a cross sectional
view of an alternative valve arrangement for use in a dispense
interface 200. In this arrangement, the dispense interface 300
comprises a sleeve valve arrangement 302.
[0108] As illustrated, the dispense interface 300 comprises a first
medicament pre-valve ullage 304 and a second medicament pre-valve
ullage 306. The first medicament pre-valve ullage 304 would contain
ullage of the first medicament residing between the cartridge
containing the first medicament and the first medicament valve 308.
Similarly, the second medicament pre-valve ullage 306 would contain
ullage of the second medicament residing between the cartridge
containing the second medicament and the second medicament valve
310.
[0109] As in the areas of 308 and 310, the flexible portion of the
elastic part is not jacked up by the outer housing of the dispense
interface 300. As such, these flexible portions are free to
flexibly move and are driven by pressure/backpressure, similar to
the valve arrangement illustrated in FIG. 9. The flexible portions
are connected to the rest of the elastic component and, in this
arrangement, do not comprise stand-alone components other solutions
in the state of the art.
[0110] The post valve ullage 312 is provided as a holding chamber
314 of the dispense interface 300. In this arrangement, both the
first and the second cartridges contained within the drug delivery
device comprise their own one-way valve that connect to a shared
post valve ullage. Once a dispenser, such as a double ended needle
assembly, is mounted to the distal end of the dispense interface,
the shared post valve ullage would be in fluid communication with
this dispenser acting as an outlet needle.
[0111] The post-valve ullage 312 has a first end 316 and a second
end 318. In this embodiment the medicaments enter the post-valve
ullage 312 through the second end 318. The end of a double ended
needle 406 can be inserted through the same end 318.
[0112] As can be further seen from FIG. 12, the ullages are
provided by the inner body 320, while the valves are positioned
between the inner body 320 and the outer body 322. Here, the drug
agents 92, 102 are guided past the post-valve ullage 312 to be
inserted into the post-valve ullage 312 at the second end 318 of
the post-valve ullage 312. A needle 406 as illustrated in FIG. 13
is usually already inserted in to the post valve ullage 312. This
results in the effect that the drug agents 92, 102 flow into the
post-valve ullage 312 substantially from the second end 318 towards
the first end 316 of the post valve ullage 312 and exit the
post-valve ullage 312 through the first end 405 of the needle 406
substantially from the first end 316 of the post valve ullage 312
in the direction of the second end 318 of the post valve ullage
312. Thus, a flow inversion is achieved in the post-valve ullage
312 and a particularly effective mixing of the drug agents 92, 102
can be achieved.
[0113] Alternatively, the dispense interface may comprise a valve
arrangement comprising a beak valve arrangement. For example, FIG.
13 illustrates a cross sectional view of a beak valve arrangement
502 for use in a dispense interface 500. As illustrated, the
dispense interface 500 comprises a first medicament pre-valve
ullage 504 and a second medicament pre-valve ullage 506. In this
arrangement, both the first and the second cartridges contained
within the drug delivery device comprise a separate own one-way
valve. For example, the first cartridge containing the primary
medicament would comprise the first one-way valve 508 and the
second cartridge containing the secondary medicament would contain
the second one-way valve 510. In this arrangement, both the first
and the second cartridges contained within the drug delivery device
comprise their own one-way valve that connect to a shared post
valve ullage 512 in form of a holding chamber 514. Once a doser,
such as a double ended needle assembly, is mounted to the distal
end of the dispense interface, the shared post valve ullage would
be in fluid communication with this dispenser acting as an outlet
needle.
[0114] In this case the drug agents enter the post-valve ullage 512
through the first end 516. As can be further seen from FIG. 13, the
first end 407 of the needle 406 is positioned substantially in the
middle of the post-valve ullage 512. Thus, while the drug agents
92, 102 enter the post valve ullage 512 at the first end 516 of the
post-valve ullage 512 and at least a part of the drug agents 92,
102 will reach the second end 518 of the post-valve ullage 512, the
drug agents 92, 102 have to exit through the first end 405 of the
needle 406 and therefore will have to flow again towards the first
end 516 of the post-valve ullage 512 to reach the center of the
post-valve ullage 512. Thus, a flow inversion is achieved in the
post-valve ullage 512 and a particularly effective mixing of the
drug agents 92, 102 can be achieved.
[0115] In particular the valves 308, 310, 508, 510 illustrated in
FIGS. 12 and 13, can be made of a material such as TPE, PTFE,
silicone or EPDM.
[0116] The term "drug" or "medicament", as used herein, means a
pharmaceutical formulation containing at least one pharmaceutically
active compound,
[0117] 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,
[0118] 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,
[0119] 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,
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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-V-
al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-
-Pro-Ser-NH2.
[0124] Exendin-4 derivatives are for example selected from the
following list of compounds: [0125] H-(Lys)4-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0126] H-(Lys)5-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0127] des Pro36 [Asp28] Exendin-4(1-39),
[0128] des Pro36 [IsoAsp28] Exendin-4(1-39), [0129] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0130] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0131] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0132] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0133] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0134] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39); or [0135] des Pro36 [Asp28] Exendin-4(1-39),
[0136] des Pro36 [IsoAsp28] Exendin-4(1-39), [0137] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0138] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0139] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0140] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0141] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0142] 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 [0143] H-(Lys)6-des Pro36 [Asp28]
Exendin-4(1-39)-Lys6-NH2, [0144] des Asp28 Pro36, Pro37,
Pro38Exendin-4(1-39)-NH2, [0145] H-(Lys)6-des Pro36, Pro38 [Asp28]
Exendin-4(1-39)-NH2, [0146] H-Asn-(Glu)5des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-NH2, [0147] des Pro36, Pro37, Pro38 [Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0148] H-(Lys)6-des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0149] H-Asn-(Glu)5-des Pro36,
Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0150]
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
[0151] H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]
Exendin-4(1-39)-NH2, [0152] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0153] H-Asn-(Glu)5-des
Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0154]
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0155] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0156]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0157] H-(Lys)6-des Pro36 [Met(O)14,
Asp28] Exendin-4(1-39)-Lys6-NH2, [0158] des Met(O)14 Asp28 Pro36,
Pro37, Pro38 Exendin-4(1-39)-NH2, [0159] H-(Lys)6-desPro36, Pro37,
Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, [0160]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0161] des Pro36, Pro37, Pro38 [Met(O)14,
Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0162] H-(Lys)6-des Pro36,
Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0163]
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0164] H-Lys6-des Pro36 [Met(O)14,
Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, [0165] H-des Asp28
Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
[0166] H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0167] H-Asn-(Glu)5-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0168] des Pro36,
Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0169] H-(Lys)6-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, [0170]
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.
[0171] 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.
[0172] 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.
[0173] Antibodies are globular plasma proteins (.about.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.
[0174] 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.
[0175] 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.
[0176] Distinct heavy chains differ in size and composition;
.alpha. and .gamma. contain approximately 450 amino acids and
.delta. 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.
[0177] 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.
[0178] 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.
[0179] 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
crystallizable 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).
[0180] 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.
[0181] Pharmaceutically acceptable solvates are for example
hydrates.
* * * * *