U.S. patent application number 15/632571 was filed with the patent office on 2017-10-12 for dispense interface with lockout element.
The applicant listed for this patent is SANOFI-AVENTIS DEUTSCHLAND GMBH. Invention is credited to Simon Lewis Bilton, James Alexander Davies, Christopher Nigel Langley, David Moore, Steven Wimpenny.
Application Number | 20170290996 15/632571 |
Document ID | / |
Family ID | 44925171 |
Filed Date | 2017-10-12 |
United States Patent
Application |
20170290996 |
Kind Code |
A1 |
Davies; James Alexander ; et
al. |
October 12, 2017 |
DISPENSE INTERFACE WITH LOCKOUT ELEMENT
Abstract
The invention is related to an apparatus comprising a dispense
interface comprising a lockout element for use with a drug delivery
device, the lockout element comprising at least one spring
component removeably maintained in a respective first position such
that when the dispense interface is first attached and then removed
from said drug delivery device, each spring component moves into a
respective second position, which respective second position is
configured to prevent said dispense interface from being reattached
to a drug delivery device.
Inventors: |
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 |
SANOFI-AVENTIS DEUTSCHLAND GMBH |
FRANKFURT AM MAIN |
|
DE |
|
|
Family ID: |
44925171 |
Appl. No.: |
15/632571 |
Filed: |
June 26, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14113392 |
Apr 30, 2014 |
9717863 |
|
|
PCT/EP2012/057680 |
Apr 26, 2012 |
|
|
|
15632571 |
|
|
|
|
61480063 |
Apr 28, 2011 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/3202 20130101;
A61M 5/19 20130101; A61M 2005/3128 20130101; A61M 5/50 20130101;
A61M 2005/3118 20130101; A61M 5/347 20130101; A61M 5/2033 20130101;
A61M 5/3286 20130101; A61M 5/31593 20130101; A61M 2205/502
20130101; A61M 5/34 20130101; A61M 2205/50 20130101 |
International
Class: |
A61M 5/50 20060101
A61M005/50; A61M 5/315 20060101 A61M005/315; A61M 5/32 20060101
A61M005/32; A61M 5/34 20060101 A61M005/34; A61M 5/19 20060101
A61M005/19; A61M 5/20 20060101 A61M005/20 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 8, 2011 |
EP |
11173266.5 |
Claims
1. An apparatus comprising: a dispense interface for use with a
drug delivery device, the dispense interface comprising a lockout
element, the lockout element comprising at least one spring
component removeably maintained in a respective first position such
that when the dispense interface is first attached and then removed
from said drug delivery device, each spring component moves into a
respective second position, which respective second position is
configured to prevent said dispense interface from being reattached
to a drug delivery device.
2. The apparatus according to claim 1, wherein each spring
component comprises a respective button spring, each respective
button spring comprising a respective set of winged tabs.
3. The apparatus according to claim 2, wherein each button spring
is an over-centering wing spring.
4. The apparatus according to claim 2, wherein each set of winged
tabs comprises three winged tabs.
5. The apparatus according to claim 2, wherein each button spring
is dome-shaped.
6. The apparatus according to claim 2, wherein each winged tab of
each respective set of winged tabs is configured to move radially
inward when the respective button spring moves into the respective
second position.
7. The apparatus according to claim 1, wherein when in the
respective second position the spring component is configured to
mechanically block said dispense interface from being reattached to
a drug delivery device.
8. The apparatus according to claim 1, wherein each spring
component is configured to be maintained in a third position while
the dispense interface is attached to the drug delivery device,
wherein in the third position the spring components are biased to
move into the second position but are prevented from moving into
the second position by the drug delivery device.
9. The apparatus according to claim 1, wherein the dispense
interface is configured to attach to the drug delivery device to
form a first fluid connection between the dispense interface and a
first reservoir of the drug delivery device, and to form a second
fluid connection between the dispense interface and a second
reservoir of the drug delivery device.
10. The apparatus according to claim 9, wherein the dispense
interface comprises a first spring component associated with the
first fluid connection, and a second spring component associated
with the second fluid connection.
11. The apparatus according to claim 1, wherein the dispense
interface comprises a mounting hub configured for releasable
attachment of a needle assembly.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Continuation of U.S. patent
application Ser. No. 14/113,392, filed Apr. 30, 2014, which is a
U.S. National Phase Application pursuant to 35 U.S.C. .sctn.371 of
International Application No. PCT/EP2012/057680 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. 11173266.5 filed Jul. 8, 2011. The entire disclosure contents
of these applications are herewith incorporated by reference into
the present application.
FIELD OF THE 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. In particular,
the present invention relates to a dispense interface with a
lockout element as for example usable in such a medical drug
delivery device.
[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] Delivering one or more medicaments through a dose dispenser
with a dispense interface can result in the contamination of the
dispense interface with traces of each medicament. This
contamination may prohibit reusing the dispense interface, for
example after a certain time or after a predetermined number of
usages, because the purity of the delivered medicaments cannot be
guaranteed. Even a user who is conscious of this problem may
inadvertently try to reuse a dispense interface because he may not
remember and may find it difficult or impossible to determine by
inspection whether a given dispense interface has in fact been used
or not.
[0019] It is therefore desirable to provide the dispense interface
with a mechanism that prevents reuse of the dispense interface with
a drug delivery device. This mechanism should be such that it is
effective in its prevention of reuse as well as safe from manual
manipulation by a user.
[0020] Thus it is an object of the invention to provide a dispense
interface for use with a drug delivery device which has a lockout
mechanism that prevents reusing this dispense interface after it
has already been used with a drug delivery device.
[0021] This object is solved by an apparatus comprising: a dispense
interface for use with a drug delivery device, the dispense
interface comprising a lockout element, the lockout element
comprising at least one spring component removably maintained in a
respective first position such that when the dispense interface is
first attached and then removed from said drug delivery device,
each spring component moves into a respective second position,
which respective second position is configured to prevent said
dispense interface from being reattached to a drug delivery
device.
[0022] The lockout element is arranged in its default state, i.e.
in its first position, such that it allows attachment of the
dispense interface to the drug delivery device. However, the
process of attaching the dispense interface to the drug delivery
device mechanically moves the lockout element such that, once the
dispense interface is detached and thereby is removed from the drug
delivery device, the lockout element mechanically blocks a
reattachment of the dispense interface to any drug delivery device
of the same or similar kind. Therefore a reuse of the dispense
interface is prevented and the risk of contamination from residual
drug components within the dispense interface eliminated.
[0023] To this end, the lockout element comprises at least one
spring component in a first position in which it does not interfere
with the attachment of the dispense interface to the drug delivery
device. There may be any number of spring components. Without loss
of generality, the further description will assume there to be a
plurality of spring components. In this first position, the spring
components are already held under tension and therefore store
potential energy. Moreover, the spring components are arranged such
that they are mechanically engaged by a part of the drug delivery
device during the attachment of the dispense interface to the drug
delivery device. This engagement moves the spring components such
that they are released from their hold, thereby permitting them to
change their position by virtue of their stored energy. This change
of position may also comprise a change of shape of the spring
components. The change of position may only affect parts of the
spring component, i.e. not all parts of the spring component may
have changed their location when the spring component is said to
have moved from the first position to a next position. In the
second position, which the spring component moves into either
directly after having left the first position or after possibly
having gone through one or more intermediate positions, the spring
components block the re-attachment of the dispense interface to any
drug delivery device of the same or similar kind. In the second
position, the spring components block tubular stubs configured to
receive the cartridge boss associated with each reservoir of the
drug delivery device.
[0024] Elaborating on the movement of the spring components to the
second position, the spring components may complete their move to
the second, blocking position only after the dispense interface has
been detached from the drug delivery device. In particular, the
spring components may be moved to an intermediate third position,
which is non-blocking, on engagement with the drug delivery device.
In this third position, the spring components may be biased to move
into the second position but may be prevented from doing so by the
still-attached drug delivery device. When the dispense interface is
detached from the drug delivery device, the spring components are
released and may fully move into the blocking second position.
[0025] Attaching the dispense interface to the drug delivery device
entails creating a fluid connection between the dispense interface
and the reservoirs of the drug delivery device storing the
medicaments to be delivered. Preferably, the dispense interface
comprises a spring component for each fluid connection to a
reservoir of the drug delivery device. In other words, the dispense
interface preferably comprises as many spring components as it has
fluid connections sockets corresponding to the cartridge bosses of
the drug delivery device.
[0026] A preferred embodiment is characterized in that each spring
component comprises a respective button spring, each respective
button spring comprising a respective set of winged tabs. The
winged tabs are preferably arranged at the circumference of the
button spring and facing a direction perpendicular to the button
spring. The winged tabs are preferably arranged to move radially
inward when the button spring is sprung.
[0027] In another preferred embodiment, each button spring is an
over-centering wing spring.
[0028] In a further preferred embodiment, each set of winged tabs
comprises three winged tabs.
[0029] In yet a further preferred embodiment, each button spring is
dome-shaped.
[0030] In another preferred embodiment, each winged tab of each
respective set of winged tabs is configured to move radially inward
when the respective button spring moves into the respective second
position.
[0031] In yet another preferred embodiment, each spring component
comprises a respective circlip spring. Each circlip spring is
essentially ring-shaped, though it may have one or more projections
in the outward or inward direction. Each circlip spring may be
arranged around a respective tubular stub, wherein each tubular
stub is configured to receive the cartridge boss associated with
each reservoir of the drug delivery device. Each circlip spring is
further configured to assume one of two positions. In the first
position, the circlip spring is extended radially outwards and has
a greater diameter. In this position, the circlip spring is in a
strained state with internal strain acting to contract the circlip
spring. In the second position, the circlip spring is contracted
and has a smaller diameter.
[0032] In a further preferred embodiment, each circlip spring is
maintained in a respective first diameter channel provided by the
dispense interface in the respective first position. In particular,
this diameter channel may be a tubular stub on the dispense
interface configured for connecting to the corresponding cartridge
boss of the medicament reservoir of the drug delivery device. This
first diameter channel may have a diameter sufficiently large to
maintain the respective circlip spring in a strained state.
[0033] In another preferred embodiment, each circlip spring is
configured to be shunted forwards into a respective second diameter
channel which is on a smaller diameter than the respective first
diameter channel when the dispense interface is attached to said
drug delivery device. Each circlip spring may be shunted forwards
by being engaged by a part of the drug delivery device on the
attachment of the dispense interface to the drug delivery device,
in particular by a cartridge boss associated with a reservoir of
the drug delivery device. Each circlip spring may be shunted
forwards by being pushed on a tubular stub in the axial direction
toward the dispense interface. The second diameter channel may be a
part of the tubular stub with a smaller diameter than the part of
the tubular stub around which the circlip spring is maintained in
the position of the circlip spring before being shunted forwards,
i.e. the first diameter channel.
[0034] In a preferred embodiment, each circlip spring is configured
to spring inwards in the radial direction when said dispense
interface is removed from said drug delivery device and thereby
detached. Because the circlip spring is, after being shunted
forewards, in a second diameter channel on a smaller diameter, the
strain on the circlip spring from being originally in the position
of greater diameter acts to contract the circlip spring to the
smaller diameter. However, as long as the dispense interface is
attached to the drug delivery device, the engaging parts of the
drug delivery device may act to maintain the circlip spring on the
first diameter, i.e. the greater diameter. Therefore the circlip
spring will contract by springing inwards when the dispense
interface is removed from the drug delivery device maintaining the
circlip spring in the greater diameter.
[0035] In a further preferred embodiment, a portion of each circlip
spring is configured to deflect sufficiently inward to shrink an
effective receptive diameter to prevent said dispense interface
from being reattached to a drug delivery device. This prevention
may occur, in particular, through a mechanical blocking effect of
the inwardly deflected portion of the circlip spring. The effective
receptive diameter may be the diameter of a tubular stub configured
for engaging its counter part, for example a cartridge boss of the
drug delivery device, and thereby creating a fluid connection with
a reservoir of the drug delivery device. There is a minimum
diameter under which the effective receptive diameter must not fall
in order for an attachment of the dispense interface to the drug
delivery device to be possible. The inwardly deflected portion of
each circlip spring may comprise a protrusion in the inward
direction.
[0036] In yet a further preferred embodiment, each circlip spring
is maintained in the respective first position by a respective tab.
The respective tab may be held in place by a tightening force
exerted by the circlip spring due to its internal strain. The
respective tab may also have a small but integral connection with
the circlip spring configured to be torn when the tab is forced
away by the engaging part of the drug delivery device.
[0037] In a preferred embodiment, each circlip spring is configured
to move into a respective locked condition upon deflection of the
respective tab during the attachment of the dispense interface to
said drug delivery device and subsequent detachment of the dispense
interface from the drug delivery device. It may be that each
circlip spring does not move upon deflection of the respective tab
as long as the drug delivery device which has deflected the
respective tab is in place and takes up the previous space of the
respective tab and that consequently each circlip spring completes
its movement into the locked condition after the dispense interface
has been detached from the drug delivery device.
[0038] In another aspect, a dispense interface for use with a drug
delivery device is provided. The dispense interface comprises a
main outer body and an inner body positioned within at least a
portion of the main outer body. The inner body may be configured
for connection to a drug delivery device and defines a first inner
body reservoir and a second inner body reservoir. The dispense
interface further comprises a first piercing needle in fluid
communication with the first inner body reservoir and positioned
for piercing a first reservoir contained within a drug delivery
device. A second piercing needle is provided by the inner body and
in fluid communication with the second inner body reservoir and
positioned for piercing a second reservoir contained with a drug
delivery device. A manifold is positioned adjacent a generally flat
surface of the inner body and comprises a fluid groove arrangement.
A valve arrangement is positioned between the inner body and the
manifold. The valve arrangement controls fluid communication of a
first fluid contained in the first cartridge and a second fluid
contained in the second cartridge by way of the fluid groove
arrangement to a holding chamber of the inner body. The dispense
interface may further comprise a lockout preventing dispense
interface reuse.
BRIEF DESCRIPTION OF THE FIGURES
[0039] 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:
[0040] FIG. 1 illustrates a perspective view of a delivery device
with an end cap of the device removed;
[0041] FIG. 2 illustrates a perspective view of the delivery device
distal end showing the cartridge;
[0042] FIG. 3 illustrates a perspective view of the delivery device
illustrated in FIG. 1 or 2 with one cartridge retainer in an open
position;
[0043] 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;
[0044] 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;
[0045] FIG. 6 illustrates a needle assembly that may be mounted on
a distal end of the delivery device;
[0046] FIG. 7 illustrates a perspective view of the dispense
interface illustrated in FIG. 4;
[0047] FIG. 8 illustrates another perspective view of the dispense
interface illustrated in
[0048] FIG. 4;
[0049] FIG. 9 illustrates a cross-sectional view of the dispense
interface illustrated in FIG. 4;
[0050] FIG. 10 illustrates an exploded view of the dispense
interface illustrated in FIG. 4;
[0051] 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;
[0052] FIG. 12 illustrates a perspective view of a dispense
interface comprising a lockout element;
[0053] FIG. 13 illustrates a cross-sectional view of the dispense
interface illustrated in FIG. 12;
[0054] FIG. 14 illustrates a perspective view of an alternative
arrangement of a dispense interface comprising a lockout
element;
[0055] FIG. 15 illustrates a cross-sectional view of the dispense
interface illustrated in FIG. 14;
[0056] FIG. 16 illustrates a cross-sectional view of a portion of
the dispense interface illustrated in FIG. 14
[0057] FIG. 17 illustrates a cross-sectional view of another
portion of the dispense interface illustrated in FIG. 14.
DETAILED DESCRIPTION
[0058] 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.
[0059] 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.
[0060] 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.
[0061] 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).
[0062] 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.
[0063] 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.
[0064] 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).
[0065] As shown in FIG. 3, a first and a second cartridge retainer
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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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).
[0070] 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.
[0071] 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:
[0072] a. a main outer body 210,
[0073] b. an first inner body 220,
[0074] c. a second inner body 230,
[0075] d. a first piercing needle 240,
[0076] e. a second piercing needle 250,
[0077] f. a valve seal 260, and
[0078] g. a septum 270.
[0079] 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.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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, 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. 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] In the following embodiments of the present invention will
be described in detail with reference to FIGS. 12 to 17.
[0098] In an example embodiment, the dispense interface can include
a lockout mechanism. Such a lockout 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.
[0099] FIG. 12 illustrates a perspective view of a dispense
interface 6005 comprising a lockout element 6000. Specifically,
FIG. 12 illustrates a perspective view of the proximal end of the
dispense interface 6005 comprising a lockout element 6000 that
comprises a first and a second button spring 6010, 6020. As
illustrated, the button springs 6010, 6020 may comprise a version
of an over-centering wing spring. In one arrangement, each of the
button springs 6010, 6020 comprise three winged tabs which can
function to lockout the lockout element 6000 and prevent the
dispense interface 6005 from re-use. For example, first button
spring 6010 may comprise three winged tabs 6015a, 6015b, 6015c and
second button spring may comprise three wing tabs 6025a, 6025b,
6025c. The first and second springs 6010, 6020 are generally dome
shaped so as to provide an over-centering force.
[0100] FIG. 13 illustrates a cross sectional view of the dispense
interface 6005 and lockout element 6000 illustrated in FIG. 12. As
illustrated, one side of the dispense interface 6005 is shown with
the button spring 6010 in the receptive condition. That is, the
three winged tabs 6015a, 6015b, 6015c of button spring 6010 reside
in an open position so as to receive a distal end of a cartridge
from the drug delivery device. The other side of the dispense
interface 6005 is shown where the second button spring 6020 resides
in the locked condition, i.e., where the three winged tabs 6025a,
6025b, 6025c reside in a locked position and therefore would not be
able to received a distal end of a cartridge form the drug delivery
device.
[0101] FIG. 14 illustrates a perspective view of an alternative
arrangement of a dispense interface 6405 comprising a lockout
element arrangement 6400. In this arrangement, the lockout element
arrangement 6400 comprises a first circlip spring 6410 and a second
circlip spring 6420.
[0102] FIG. 15 illustrates a cross sectional view of the dispense
interface 6405 and lockout element arrangement 6400 illustrated in
FIG. 14. In this particular arrangement, it is conceptually similar
to the lockout element 6000 illustrated in FIGS. 12-13 and
discussed herein. In the arrangement illustrated in FIGS. 14-15, a
pair of radial clips 6410, 6420 are held open within a large
diameter channel of the dispense interface 6405. A pair of
cartridge bosses on the drug delivery device (not illustrated) may
be received into these clips 6410, 6420. When the dispense
interface 6405 comprising the lockout element 6400 is fitted onto
the cartridge bosses, the clips are contacted and are shunted
forwards (in a distal direction) into a second channel which is on
a smaller diameter. In this position where the clip resides in a
second channel of smaller diameter, the clips 6410, 6420 are
activated. Thereafter, once the drug delivery device is removed,
the clips spring inwards. Bend portions of the clips deflect
sufficiently inwards to shrink the effective receptive boss
diameter, forming a lockout condition of the clips. For example, as
illustrated in FIG. 15, the first clip spring 6410 remains in the
locked condition while the second clip spring 6420 remains in the
receptive condition.
[0103] FIGS. 16 and 17 illustrate portions of the dispense
interface 6405 illustrated in FIG. 15. Specifically, FIG. 16
illustrates a top perspective view of the second clip 6420 of the
lockout element 6400 residing in the receptive condition.
Specifically, FIG. 17 illustrates a top perspective view of the
first clip 6410 of the lockout element 6400 illustrated in the
locked condition with the bend portions of the clips deflecting
sufficiently inwards.
[0104] Alternative embodiments for holding the spring in an
initially open condition could also be used. As just one example, a
tab feature which initially sits between the clip ends may be
deflected away from the clip mouth during fitment of the dispense
interface onto the drug delivery device.
[0105] The term "drug" or "medicament", as used herein, means a
pharmaceutical formulation containing at least one pharmaceutically
active compound,
[0106] 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,
[0107] 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,
[0108] 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,
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
[0113] Exendin-4 derivatives are for example selected from the
following list of compounds: [0114] H-(Lys)4-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0115] H-(Lys)5-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0116] des Pro36 [Asp28] Exendin-4(1-39),
[0117] des Pro36 [IsoAsp28] Exendin-4(1-39), [0118] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0119] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0120] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0121] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0122] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0123] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39); or [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), 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 [0132] H-(Lys)6-des Pro36 [Asp28]
Exendin-4(1-39)-Lys6-NH2, [0133] des Asp28 Pro36, Pro37,
Pro38Exendin-4(1-39)-NH2, [0134] H-(Lys)6-des Pro36, Pro38 [Asp28]
Exendin-4(1-39)-NH2, [0135] H-Asn-(Glu)5des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-NH2, [0136] des Pro36, Pro37, Pro38 [Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0137] H-(Lys)6-des Pro36, Pro37, Pro38
[Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0138] H-Asn-(Glu)5-des Pro36,
Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0139]
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
[0140] H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25]
Exendin-4(1-39)-NH2, [0141] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0142] H-Asn-(Glu)5-des
Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0143]
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0144] H-(Lys)6-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0145]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0146] H-(Lys)6-des Pro36 [Met(O)14,
Asp28] Exendin-4(1-39)-Lys6-NH2, [0147] des Met(O)14 Asp28 Pro36,
Pro37, Pro38 Exendin-4(1-39)-NH2, [0148] H-(Lys)6-desPro36, Pro37,
Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, [0149]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0150] des Pro36, Pro37, Pro38 [Met(O)14,
Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0151] H-(Lys)6-des Pro36,
Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0152]
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0153] H-Lys6-des Pro36 [Met(O)14,
Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, [0154] H-des Asp28
Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
[0155] H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0156] H-Asn-(Glu)5-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0157] des Pro36,
Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0158] H-(Lys)6-des Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2, [0159]
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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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).
[0169] 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.
[0170] Pharmaceutically acceptable solvates are for example
hydrates.
* * * * *