U.S. patent application number 14/666671 was filed with the patent office on 2015-07-09 for piston for a cartridge and piston rod for a drug delivery device.
The applicant listed for this patent is SANOFI-AVENTIS DEUTSCHLAND GMBH. Invention is credited to Michael Jugl, Martin Otten.
Application Number | 20150190581 14/666671 |
Document ID | / |
Family ID | 42173767 |
Filed Date | 2015-07-09 |
United States Patent
Application |
20150190581 |
Kind Code |
A1 |
Jugl; Michael ; et
al. |
July 9, 2015 |
PISTON FOR A CARTRIDGE AND PISTON ROD FOR A DRUG DELIVERY
DEVICE
Abstract
The present invention relates to a piston for a cartridge for a
drug delivery device comprising: at least one annular sealing
surface to radially abut against an inner side wall of a cartridge,
a distal surface to confine a drug receiving volume of the
cartridge, a thrust receiving surface adapted to receive a thrust
exerting plunger of a drug delivery device for displacing the
piston in a proximal direction relative to the side wall, wherein
the thrust receiving surface comprises numerous centering elements
protruding from the thrust receiving surface towards the plunger
and wherein the centering elements comprise an outer shape and
geometry that matches with a corresponding receptacle of the
plunger, and wherein the centering elements are arranged and
aligned on the circumference of an imaginary annular or circular
structure.
Inventors: |
Jugl; Michael; (Frankfurt am
Main, DE) ; Otten; Martin; (Frankfurt am Main,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI-AVENTIS DEUTSCHLAND GMBH |
Frankfurt am Main |
|
DE |
|
|
Family ID: |
42173767 |
Appl. No.: |
14/666671 |
Filed: |
March 24, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13516062 |
Sep 12, 2012 |
|
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PCT/EP2010/069869 |
Dec 16, 2010 |
|
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14666671 |
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Current U.S.
Class: |
604/228 |
Current CPC
Class: |
A61M 5/31515 20130101;
A61M 5/31583 20130101; A61M 5/31513 20130101; A61M 5/31535
20130101 |
International
Class: |
A61M 5/315 20060101
A61M005/315 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2009 |
EP |
09180005.2 |
Claims
1. A piston for use in a drug containing cartridge configured for
use in a drug delivery device comprising, a) a distal end face, a
proximal thrust receiving surface and a radial sealing surface that
is configured to engage an inner sidewall of a cartridge to provide
a leak proof seal; b) at least four centering elements protruding
proximally from the thrust receiving surface, where the centering
elements, i) are arranged on the thrust receiving surface in a
pattern that matches a geometric shape of a receptacle on a drug
delivery device plunger having a distal facing end face; ii)
protrude outwardly a distance less than or equal to a depth of the
receptacle such that the distal facing end face of the plunger is
in contact with the thrust receiving surface when the plunger and
piston abut; and iii) fit within the receptacle when the plunger
and piston abut.
2. The piston according to claim 1, wherein the centering elements
contact the receptacle during abutment such that a radial offset in
position or orientation between the plunger and piston is corrected
causing the distal facing end face of the plunger to directly
contact against the thrust receiving surface of the piston.
3. The piston according to claim 1, wherein the at least four
centering element is integrally formed with a body of the
piston.
4. The piston according to claim 1 further comprising only four
centering elements.
5. The piston according to claim 4, wherein the pattern of the four
centering elements is equivalent to headings of a compass.
6. The piston according to claim 4, wherein the pattern of the four
centering elements is a circular.
7. The piston according to claim 1, wherein the centering elements
are arranged and aligned on the circumference of an imaginary
annular or circular structure in the plane of the thrust receiving
surface.
8. A piston and plunger combination for use in a drug delivery
device comprising, a) a piston having a body comprising a distal
end face and a proximal thrust receiving surface; b) at least four
centering elements protruding proximally from the thrust receiving
surface, c) a plunger having a distal facing end face; and d) a
receptacle on the distal facing end face having a geometric shape
and depth, wherein the centering elements are arranged on the
thrust receiving surface in a pattern that matches the geometric
shape of the receptacle and protrude outwardly from the thrust
receiving surface a distance less than or equal to the depth of the
receptacle such that the distal facing end face is in contact with
the thrust receiving surface when the plunger and piston abut.
9. The piston and plunger combination of claim 8 where the piston
further comprises a radial sealing surface that is configured to
engage an inner sidewall of a cartridge to provide a leak proof
seal.
10. The piston and plunger combination of claim 8 where the
geometric shape and depth of the receptacle is configured such that
the centering elements are completely received in the receptacle
when the piston and plunger abut.
11. The piston and plunger combination of claim 8 where the
geometric shape and depth of the receptacle are configured such
that if the piston and plunger are radially offset from one another
then the plunger or the piston are subjected to a radially directed
centering movement when the centering elements match with the
receptacle of the plunger to laterally align the piston and
plunger.
12. The piston and plunger combination of claim 8 where the
geometric shape of the receptacle is a substantially U- or V-shaped
groove of circular geometry as viewed in a plane parallel to the
distal facing end face.
13. The piston and plunger combination of claim 8 where the pattern
of the centering elements and the shape of the receptacle is
circular.
14. The piston and plunger combination of claim 8 where the thrust
receiving surface has only four centering elements protruding
proximally that are arranged in a pattern that is equivalent to
headings of a compass.
15. The piston and plunger combination of claim 8 where at least
one centering element is a spacer configured to prevent mutual
adhering of like pistons when the pistons are mass produced.
16. The piston and plunger combination of claim 8 where at least
one centering element is a knob-like protrusion.
17. The piston and plunger combination of claim 8 where the
centering elements when as viewed in a plane parallel to the thrust
surface comprise one or more of a circular, oval, arcuate, or
rectangular shape.
18. The piston and plunger combination of claim 8 where the
receptacle has a radius of curvature and the centering elements
comprise bent rectangles that match the radius of curvature of the
receptacle.
19. The piston and plunger combination of claim 8 where at least at
least one centering element is tapered in a direction towards the
plunger.
20. The piston and plunger combination of claim 8 where the
centering elements are integrally formed with the body of the
piston.
21. The piston and plunger combination of claim 8 where the plunger
comprises an axially displaceable piston rod and a radially
extending bearing disc.
22. The piston and plunger combination of claim 21 where the
bearing disc is rotatably supported at a distal end portion of the
piston rod and has a distal end face comprising the receptacle.
23. A drug containing cartridge comprising a piston having a) a
distal end face, a proximal thrust receiving surface and a radial
sealing surface that is configured to engage an inner sidewall of a
cartridge to provide a leak proof seal; b) a plurality of centering
elements protruding proximally from the thrust receiving surface,
where the centering elements, i) are arranged on the thrust
receiving surface in a pattern that matches a geometric shape of a
receptacle on a drug delivery device plunger having a distal facing
end face; ii) protrude outwardly a distance less than or equal to a
depth of the receptacle such that the distal facing end face of the
plunger is in contact with the thrust receiving surface when the
plunger and piston abut; and iii) fit within the receptacle when
the plunger and piston abut.
24. A drug delivery device comprising, a) a piston having a body
comprising a distal end face and a proximal thrust receiving
surface; b) a plurality of centering elements protruding proximally
from the thrust receiving surface, c) a plunger having a distal
facing end face; and d) a receptacle on the distal facing end face
having a geometric shape and depth, wherein the centering elements
are arranged on the thrust receiving surface in a pattern that
matches the geometric shape of the receptacle and protrude
outwardly from the thrust receiving surface a distance less than or
equal to the depth of the receptacle such that the distal facing
end face is in contact with the thrust receiving surface when the
plunger and piston abut.
25. A method of correcting a radial offset between a piston and a
plunger both contained in an assembled drug delivery device
comprising, a) providing a piston contained in a cartridge having a
distal end face and a proximal thrust receiving surface, where the
distal end face has a plurality of centering elements protruding
proximally from the thrust receiving surface; b) providing a
plunger within a housing of the drug delivery device, the plunger
having a distal facing end face comprising a receptacle on the
distal facing end face having a geometric shape and depth, where
the centering elements are arranged on the thrust receiving surface
in a pattern that matches the geometric shape of the receptacle,
where the centering elements protrude outwardly from the thrust
receiving surface at a depth to match the depth of receptacle such
that the distal facing end face is in contact with the thrust
receiving surface when the plunger and piston abut; and c) abutting
the piston and the plunger to engage the centering elements with
the receptacle such that a radial offset in position or orientation
between the plunger and piston is corrected causing the distal
facing end face of the plunger to directly contact and abut against
the thrust receiving surface of the piston.
26. The method of claim 25 where the engaging of the centering
elements with the receptacle further comprises contacting at least
one beveled lateral surface of a centering element with a
correspondingly lateral surface of receptacle to cause radial
alignment of the piston and the plunger.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 13/516,062, filed Sep. 12, 2012, which is a is
a U.S. National Phase Application pursuant to 35 U.S.C. .sctn.371
of International Application No. PCT/EP2010/069869 filed Dec. 16,
2010, which claims priority to European Patent Application No.
09180005.2 filed on Dec. 18, 2009. The entire disclosure contents
of these applications are herewith incorporated by reference into
the present application.
FIELD OF THE INVENTION
[0002] The present invention generally relates to a piston being
slidably disposed in a cartridge that contains a medicinal product
to be dispensed by means of a drug delivery device, such as a
pen-type injector. Moreover, the invention relates to a
thrust-transferring interface between a cartridge's piston and a
plunger of the drug delivery device being adapted to exert thrust
to said piston.
BACKGROUND
[0003] User operated drug delivery devices are as such known in the
prior art. They are typically applicable in circumstances, in which
persons without formal medical training, i.e., patients, need to
administer an accurate and predefined dose of a medicinal product,
such as heparin or insulin. In particular, such devices have
application, where a medicinal product is administered on a regular
or irregular basis over a short term or long-term period.
[0004] In order to accommodate with these demands, such devices
have to fulfil a number of requirements. First of all, the device
must be robust in construction, yet easy to use in terms of
handling and in understanding by the user of its operation and the
delivery of the required dose or medicament. The dose setting must
be easy and unambiguous. Where the device is to be disposable
rather than reusable, the device should be inexpensive to
manufacture and easy to dispose. Moreover, the device should be
suitable for recycling. To meet these requirements, the number of
parts required to assemble the device and the number of material
types the device is made from need to be kept to a minimum.
[0005] Such pen-typed injectors are typically adapted to receive a
replaceable and/or disposable cartridge containing the medicinal
product to be dispensed by means of the device. The cartridge
comprises an outlet to be coupled with a piercing element, e.g. an
injection needle, a cannula or the like in a fluid transferring
way. Further and in order to expel a predefined dose of the
medicinal product, a plunger of a drug delivery device is adapted
to act on the piston for displacing said piston by a predefined
distance in distal, thus dose-dispensing direction.
[0006] FIG. 1 shows a cross-sectional illustration of a piston 16
slidably disposed inside a circumferential cylindrical wall 24 of a
cartridge 23. The cartridge 23 is arranged inside a drug delivery
device that comprises a proximal housing component 20 and a
cartridge holder 22. The housing 20 accommodates a not further
illustrated drive mechanism, that serves to drive a piston rod 10
and a bearing disc 12 in a distal axial direction, hence downward
in the illustration of FIG. 1. For this purpose, the bearing disc
12 is rotatably mounted on a lower, hence distally located end
section of the piston rod 10. The radial dimensions of the bearing
disc 12 substantially match with the size of the proximal end face
of the piston 16.
[0007] The piston 16 comprises two annular sealing surfaces 25
radially abutting against the inner side wall 24 of the cartridge
23. In this way, the piston 16 provides a durable and leak-proof
seal for the medicinal product contained in the cartridge 23. As
can be seen in the cross-section of FIG. 1 and as further
illustrated in a top view illustration of FIG. 2, the thrust
receiving surface comprises four rectangularly shaped distance
elements, which in the course of a mass production process are
adapted to prevent mutual adhering of pistons, e.g. in a feeding
arrangement.
[0008] In the illustration of FIG. 1, the bearing disc 12 and the
proximal end face, the thrust receiving surface of the piston 16,
are not yet in mutual contact. During dose dispensing, the piston
rod 10 typically becomes subject to a rotative movement. Due to a
threaded engagement with a radially inwardly protruding thread 18,
the piston rod 10 is displaced in distal direction when rotated.
Consequently, the bearing disc 12 gets in direct contact with the
proximally located thrust receiving surface of the piston 16 and in
response to a further applied thrust, the piston 16 becomes
displaced in distal direction, that is downwards in FIG. 1.
[0009] In practice, due to manufacturing and assembly tolerances
radial position of the piston rod 10 and/or the bearing disc 12 may
vary within certain limits. Hence, a piston rod 10 and/or a bearing
disc 12 can be radially displaced with respect to the center of the
piston 16. If not properly aligned, it may occur, that the force
provided by the piston rod 10 and the bearing disc 12 is
non-centrically transferred to the piston 16. Such radial offset
may in turn lead to a cant or tilt of the piston 16, which is
flexibly deformable to a certain extent. As a consequence, a
displacement force required for distally displacing the piston 16
may substantially rise. Additionally, also the dosing accuracy may
decrease when a distally directed driving force is non-centrally
transferred to the piston 16.
[0010] Also, since the distance elements 14 protrude from the
proximal end face of the piston 16, thrust being applied to the
piston 16 is entirely received by the distance elements 14, which,
as a consequence may become squeezed. However, such point stresses
and squeezing effects may further have a negative impact on the
dosing accuracy of the drug delivery device and its drive
mechanism.
SUMMARY
[0011] It is therefore an object of the present invention to
provide an improved piston for a cartridge as well as an improved
plunger of a drug delivery device interacting with such pistons. In
particular, the invention focuses on the plunger-piston interface
of cartridges and drive mechanisms of drug delivery devices,
preferably of pen-injector type. It is a further aim of the present
invention to prevent non-centrally directed force transmission
towards a cartridge's piston. As a further object, the invention
aims to provide an improved dosing accuracy.
[0012] The present invention provides a piston for a cartridge for
a drug delivery device, wherein the piston comprises at least one
annular sealing surface to radially abut against an inner side wall
of a cartridge, being typically of cylindrical shape. The piston is
adapted to be slidably disposed in the cartridge and to provide a
durable and leak-proof seal. The cartridge itself is typically
designed as carpule or vial, in which the piston is slidably
disposed for the purpose of expelling a liquid content of the
cartridge via an outlet located at an opposite, hence, distal end
portion of the cartridge.
[0013] The piston further comprises a thrust receiving surface,
which is adapted to receive a thrust exerting plunger of a drug
delivery device. When in abutment position, the plunger serves to
displace the piston in a distal direction relative to the side wall
of the cartridge, thus expelling a pre-defined dose of the
medicinal fluid. Opposite its thrust receiving surface, the piston
comprises a distal surface adapted to confine a drug receiving
volume of the cartridge.
[0014] The thrust receiving surface, which in an assembly
configuration of the cartridge inside a drug delivery device faces
towards a plunger, comprises numerous centering elements protruding
from the thrust receiving surface towards the plunger. Said
centering elements further comprise an outer shape and geometry
that substantially matches with a corresponding receptacle of the
plunger. Typically, axial and lateral shape of the centering
elements and the corresponding receptacle match in such a way, that
the centering elements can be almost entirely inserted into the
receptacle. In other words, the receptacle of the plunger comprises
such a shape and geometry, that the centering elements protruding
from the thrust receiving surface of the piston can be entirely
received therein, thereby providing mutual lateral alignment of
piston and plunger.
[0015] Preferably, the radial position and orientation of the
centering elements on the thrust receiving surface of the piston
corresponds to the radial position and orientation of the
receptacle on the plunger, provided that plunger and piston are
mutually centered. In this way, any manufacturing or assembly
tolerances can be inherently compensated upon insertion of the
centering element into its corresponding receptacle in the plunger.
In case that after assembly of the drug delivery device piston and
plunger are positioned at a certain radial offset, by moving the
plunger in distal direction, the plunger and/or the cartridge
preferably become subject to a radially directed centering movement
when the centering elements match with the corresponding receptacle
of the plunger.
[0016] The centering elements are arranged and aligned on the
circumference of an imaginary annular or circular structure in the
plane of the thrust receiving surface.
[0017] The circular structure may be circular-symmetric but may
also be oval or elliptical. By making use of such a circular
arrangement, mutual centering and alignment of piston and plunger
can be easily attained when the circular structure is inherently
symmetric to the centre of the thrust receiving surface.
[0018] In a preferred embodiment, the centering elements and/or the
circular structure corresponds with a circular shape of the
receptacle of the plunger. In this way, not only the structure and
shape of numerous centering elements but also their mutual distance
and alignment matches with the receptacle of the plunger.
[0019] In this embodiment, the at least one centering element may
also comprise a rectangular and/or arcuate shape in a plane
parallel to the thrust receiving surface. Further, it is of
particular benefit, when various centering elements are arranged at
a distance with respect to each other on the circumference of said
imaginary circular or annular structure.
[0020] Each of the centering elements may for instance comprise a
somewhat rectangular shape, wherein each centering element is
slightly bended according to the radius and circumference of the
imaginary circular structure.
[0021] By having a circular shaped receptacle or groove on the
plunger and by having numerous centering elements distributed along
the circumference of the imaginary circle, a mutual radial
centering of piston and plunger as well as a mutual orientation in
the transverse plane can be achieved irrespective on the
orientation of the piston and its centering elements in the plane
of the thrust receiving surface.
[0022] Furthermore, and according to another preferred aspect, the
centering elements comprise an arcuate shape in a plane parallel to
the thrust receiving surface. Hence, the shape of at least some,
preferably of all centering elements matches with the shape and
geometry of the ring-like or annular receptacle of the plunger.
This way, when plunger and piston are arranged with a slight
lateral offset, almost all available centering elements contribute
in a rather similar way to a mutual alignment and centering of
piston and plunger.
[0023] According to another preferred embodiment of the invention,
the at least one centering element is integrally formed with a body
of the piston. Typically, the piston is manufactured by injection
moulding. It may comprise thermoplastic materials and/or natural or
synthetic rubber. At least one of the centering elements may
further act as a spacer or distance element that serves to prevent
mutual adhering of pistons in the course of a mass production
process. Said at least one particular centering element comprises a
knob-like shape.
[0024] In a further preferred embodiment, at least one centering
element is tapered in direction towards the plunger. Accordingly,
also the receptacle provided in the plunger comprises a
corresponding tapered cross-section, which allows to entirely
receive the centering element therein.
[0025] In a further preferred embodiment, the at least one
centering element comprises a bevelled lateral surface. Since the
receptacle is correspondingly shaped, by way of such bevelled
surfaces, a radial adjustment of piston and plunger can be attained
when mutually corresponding bevelled surfaces of receptacle and
centering element get in contact in the course of an axially and
distally directed displacement of the plunger.
[0026] Preferably, the bevelled lateral surface of the at least one
centering element is oriented at an angle of 20.degree. to
80.degree. with respect to the plane of the thrust receiving
surface. More preferably, the bevelled lateral surface of the
centering element is oriented at an angle between 30.degree. to
60.degree., most preferably, the angle is around 45.degree..
[0027] Furthermore, it is beneficial, when at least one centering
element is substantially triangular or convex in shape in a plane
perpendicular to the thrust receiving surface. Hence, the bevelled
lateral surface does not necessarily have to be rectilinear. It can
be bended, such as to facilitate mutual radial alignment of piston
and plunger in the course of a distally directed movement of the
plunger.
[0028] According to another preferred embodiment of the invention,
the ratio of at least one centering element's axial extension, that
is the extension substantially perpendicular to the thrust
receiving surface, versus its radial expansion, that is the
expansion parallel to the plane of the thrust receiving surface, is
larger or equal than 0.6. Such a ratio is particularly beneficial
for the purpose of radially centering plunger and piston or
cartridge in the course of a distally directed movement of the
plunger towards the piston.
[0029] In another independent aspect, the invention further relates
to a plunger of a drive mechanism of a drug delivery device, such
as a pen-type injector. The plunger comprises an end face adapted
to but against a thrust receiving surface of a piston being
slidably disposed in a drug containing cartridge. The end face of
the plunger facing towards the piston comprises at least one
receptacle being adapted to receive a centering element that
protrudes from the thrust receiving surface of the piston.
[0030] The receptacle of the sface as well as the centering element
protruding from the piston's thrust receiving surface mutually
match in size, shape and geometry. Also, the receptacle comprises a
somewhat circular or annular shape that corresponds with the
position and/or alignment of the centering element provided on the
thrust receiving surface. In this way, an eventual radial offset in
position or orientation of plunger and/or piston or cartridge can
be compensated in the course of bringing plunger and piston in a
mutual abutment configuration.
[0031] When shape and geometry of the receptacle matches with the
shape and geometry and/or alignment of the piston's centering
element, the end face of the plunger may almost entirely but
against the thrust receiving surface of the piston. In this way,
thrust provided by the plunger can be evenly distributed across the
plunger-piston-interface. Also, point stresses as they are arising
in the prior art and their negative impact on dosing accuracy can
be effectively reduced.
[0032] In preferable embodiments, the receptacle disposed on the
end face of the plunger comprises a substantially U- or V-shaped
groove of circular geometry in the plane of the end face. By having
a circular symmetric receptacle, a plurality of centering elements
spaced apart from each other and being arranged on an imaginary
circumference of a corresponding circle can be inserted into said
receptacle, irrespective of the orientation of the piston in the
plane of its thrust receiving surface.
[0033] According to still another preferred embodiment, the plunger
comprises an axially displaceable piston rod and a radially
extending bearing disc. The bearing disc is rotatably supported at
a distal end portion of the piston rod. Preferably, the bearing
disc comprises the receptacle at its end face pointing towards the
piston, when the drug delivery device is finally assembled.
[0034] In a further independent aspect the invention also refers to
a cartridge for a drug delivery device that comprises a
substantially cylindrical cartridge body providing a drug receiving
volume at least partially filled with a medicament and being sealed
by means of a piston as described above. The medicament is
typically intended for injection into biological tissue of a
patient.
[0035] Moreover, the invention also refers to a drug delivery
device for dispensing a pre-defined amount of a liquid drug and
being further adapted to receive a cartridge having a piston as
described above. The drug delivery device further comprises a drive
mechanism having a plunger comprising at least one receptacle being
adapted to receive a centering element protruding from a thrust
receiving surface of the piston of said cartridge.
[0036] The term "medicament", as used herein, means a
pharmaceutical formulation containing at least one pharmaceutically
active compound,
[0037] 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, a antibody,
an enzyme, an antibody, a hormone or an oligonucleotide, or a
mixture of the above-mentioned pharmaceutically active
compound,
[0038] 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,
[0039] 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,
[0040] 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.
[0041] 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.
[0042] 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.-carboxyheptadecanoyl) human insulin.
[0043] 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-Gl-
u-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly--
Ala-Pro-Pro-Pro-Ser-NH2.
[0044] Exendin-4 derivatives are for example selected from the
following list of compounds: [0045] H-(Lys)4-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0046] H-(Lys)5-des Pro36, des Pro37
Exendin-4(1-39)-NH2, [0047] des Pro36 [Asp28] Exendin-4(1-39),
[0048] des Pro36 [IsoAsp28] Exendin-4(1-39), [0049] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0050] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0051] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0052] des Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0053] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0054] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39); or [0055] des Pro36 [Asp28] Exendin-4(1-39),
[0056] des Pro36 [IsoAsp28] Exendin-4(1-39), [0057] des Pro36
[Met(O)14, Asp28] Exendin-4(1-39), [0058] des Pro36 [Met(O)14,
IsoAsp28] Exendin-4(1-39), [0059] des Pro36 [Trp(O2)25, Asp28]
Exendin-4(1-39), [0060] Pdes Pro36 [Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0061] des Pro36 [Met(O)14 Trp(O2)25, Asp28]
Exendin-4(1-39), [0062] des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28]
Exendin-4(1-39), [0063] wherein the group -Lys6-NH2 may be bound to
the C-terminus of the Exendin-4 derivative;
[0064] or an Exendin-4 derivative of the sequence [0065]
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2, [0066] des
Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, [0067] H-(Lys)6-des
Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2, [0068] H-Asn-(Glu)5des
Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2, [0069] des Pro36,
Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0070]
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0071] H-Asn-(Glu)5-des Pro36, Pro37,
Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0072] H-(Lys)6-des Pro36
[Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2, [0073] H-des Asp28
Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2, [0074]
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-NH2, [0075] H-Asn-(Glu)5-des Pro36, Pro37, Pro38
[Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, [0076] des Pro36, Pro37,
Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0077]
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0078] H-Asn-(Glu)5-des Pro36, Pro37,
Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0079]
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
[0080] des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
[0081] H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-NH2, [0082] H-Asn-(Glu)5-des Pro36, Pro37, Pro38
[Met(O)14, Asp28] Exendin-4(1-39)-NH2, [0083] des Pro36, Pro37,
Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0084]
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]
Exendin-4(1-39)-(Lys)6-NH2, [0085] H-Asn-(Glu)5 des Pro36, Pro37,
Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0086]
H-Lys6-des Pro36 [Met(O)14, Trp(02)25, Asp28]
Exendin-4(1-39)-Lys6-NH2, [0087] H-des Asp28 Pro36, Pro37, Pro38
[Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2, [0088] H-(Lys)6-des
Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, [0089]
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(1-39)-NH2, [0090] des Pro36, Pro37, Pro38 [Met(O)14,
Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2, [0091] H-(Lys)6-des
Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]
Exendin-4(S1-39)-(Lys)6-NH2, [0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] Pharmaceutically acceptable solvates are for example
hydrates.
[0097] It will be apparent to those skilled in the art that various
modifications and variations can be made to the present invention
without departing from its spirit and scope. Further, it is to be
noted, that any reference signs used in the appended claims are not
to be construed as limiting the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0098] Without limitation, the present invention will be explained
in greater detail below in connection with preferred embodiments
and with reference to the drawings in which:
[0099] FIG. 1 illustrates a cross-section of a
plunger-piston-interface region inside a pen-type injector
according to the prior art,
[0100] FIG. 2 illustrates a top view of the piston according to
FIG. 1,
[0101] FIG. 3 shows a cross section of a plunger-piston-interface
region according to the present invention,
[0102] FIG. 4 in a perspective illustration shows a piston
according to the present invention,
[0103] FIG. 5 shows a triangular-shaped centering element in
cross-section,
[0104] FIG. 6 shows a configuration of centering elements with
respect to corresponding grooves in a bearing disc prior to mutual
abutment,
[0105] FIG. 7 is illustrative of the interface according to FIG. 6,
wherein the bearing disc is radially offset but in contact with the
centering element and
[0106] FIG. 8 shows the interface according to FIGS. 6 and 7 when a
final abutment position has been reached.
DETAILED DESCRIPTION
[0107] The enlarged illustration of FIG. 3 shows a drug delivery
device in cross-section in a middle section, where a plunger buts
against a proximal end face 40 of a piston 36. The drug delivery
device as illustrated comprises a housing 20 and a cartridge holder
22. The cartridge holder 22 is adapted to receive a cartridge 33
having a substantially cylindrical side wall 24. Inside the
cartridge 33, a piston 36 is slidably disposed. The piston 36
comprises two sealing surfaces 35 radially abutting against the
inner side wall 24 of the cartridge 33. In this way, the piston 36
provides a durable and leak-proof seal for a drug receiving volume
of the cartridge 33, which is confined in proximal direction by the
lower, hence distal end face 42 of the piston 36.
[0108] Opposite its distal surface 42, the piston 36 comprises
numerous centering elements 34, which according to the illustration
of FIG. 4 are of substantially rectangular shape. The centering
elements 34 are integrally formed with the body 36 of the piston,
e.g. by way of injection moulding. The centering elements 34 are
also arranged on the circumference of an imaginary circle.
Accordingly, the centering element 34 are slightly bended, so as to
follow the circumference of the imaginary circle. The center point
of the imaginary circle typically ideally matches and overlaps with
the center point of the piston 36 itself.
[0109] As further illustrated in the cross-section of FIG. 3, the
plunger of the drug delivery device comprises a piston rod 10
threadedly engaged with a thread 18 being integrally formed with
the housing 20. At the lower, distal end of the piston rod 10 there
is rotatably mounted a bearing disc 32. At its distal surface, the
bearing disc 32 comprises a circumferential groove 38, which is
adapted to entirely receive the knob-like centering elements 34
protruding from the thrust receiving surface 40 of the piston
36.
[0110] In the illustrations of FIGS. 3 and 4, the groove 38 is
somewhat U-shaped and the corresponding centering elements 34 of
the piston 36 feature a convex shape in a plane perpendicular to
the thrust receiving surface 40. Since shape and geometry of
centering elements 34 matches with the shape and geometry of the
receptacle 38, a mutual radial alignment of piston 36 and cartridge
33 with respect to the plunger 10, 32 can be achieved as soon as
the piston rod 10 is brought into contact with the piston 36.
[0111] Since the receptacle 38 provided in the end face 44 of the
bearing disc 32 is of circular symmetric shape, a mutual radial
centering and alignment of piston 36 or cartridge 33 and/or bearing
disc 32 and piston rod 10 can be achieved irrespective of the
rotational orientation of the cartridge 33 or its piston 36.
[0112] In FIG. 5, a centering element 34 is separately illustrated
in cross-section. Here, the centering element 34 is of
substantially triangular shape. It comprises a radial extension x
and an axial extension y. In preferred embodiments, the ratio of
axial dimensions y to radial dimensions x of the centering element
34 is larger or equal than 0.6. Additionally, as illustrated in
FIG. 5, the triangular shaped centering element 34 comprises two
bevelled lateral surfaces 46.
[0113] Since size, shape and geometry of centering elements 34 and
corresponding receptacle 38 have to match, in this case also the
receptacle 38 of the bearing disc 32 comprises a V-shaped contour
as illustrated in FIGS. 6 through 8.
[0114] As shown in the course of FIGS. 6 through 8, the centering
element 34 and its corresponding receptacle 38 formed in the
bearing disc 32 are slightly offset in radial direction by a
distance 48. When the piston rod 10 is further displaced in distal
direction, hence towards the piston 36, mutually corresponding
bevelled surfaces 46, 39 of centering element 34 and receptacle 38
get in contact as depicted in FIG. 7. A further movement of the
bearing disc 32 in distal direction, hence downward in FIG. 7, then
automatically leads to a mutual radial centering of bearing disc 32
and piston 36. As indicated by the arrow pointing to the left in
FIG. 7, the bearing disc 32 and/or its interconnected piston rod 10
become subject to a movement to the left.
[0115] Finally, when an end configuration has almost been reached,
as illustrated in FIG. 8 has been reached, piston 36 and bearing
disc 32 are almost perfectly aligned in radial direction with
respect to each other. Since the depth of the receptacle 38
corresponds to the axial protrusion of the centering element 34,
the distal end face 44 of the bearing disc 32 directly abuts
against the thrust receiving surface 40 of the piston 36 across a
comparatively large surface area. Hence, when a mutual centered
configuration as illustrated in FIG. 8 has been reached, thrust
exerted by the piston 10 can be evenly and homogeneously
transferred to the piston 36 almost across the entire thrust
receiving surface 40.
[0116] In this way point stresses can be reduced and the piston 36
is less prone to inadvertent tilt or cant during dose dispensing.
This way, the driving force required to shift the piston 36 in
distal direction can be kept in a comparatively moderate range.
* * * * *