This document is substantialy identical to
the Japanese Application of the Patent of
this case.
METHOD AND DEVICE FOR INJECTION
This invention relates to a method and a
device for injection, especially for use
ambulatory treatment. More specifically,
the invention relates to a method and a device
by means of which an injection solution of
a substance is prepared immediately before
the injection, or, in the preparation of
several doses, before the first injection.
Injection devices for use in ambulatory treatment
where the medicament is present in a solution
are previously known and have been widely
used in, for example, insuline treatment
of diabetes. Such devices are usually built
so that the patient himself can easily assemble
a cylinder ampoule for one or more doses,
an injection cannula and a dosing device
in a suitable holder and thereafter give
himself easily the required injection. In
the device it is also easy to exchange used
ampoules and cannulas for new ones. In an
assembled state, such injection devices are
often shaped like a fountain-pen and can
be easily brought along by the patient.
Moreover, so-called dual-chamber or mixing
containers or cylinder ampoules are also
known for preparation of solutions of sensitive
substances immediately before the injection.
Such containers are divided into two chambers
separated by a movable wall or piston. The
sensitive medicament substance is present
in the front chamber in a dry, usually freeze-dried
state and the front end of the front chamber
is sealed by a wall penetrable to an injection
cannula. The liquid intended to dissolve
the sensitive substance before the injection
is present in the rear chamber. The two chambers
are separated by a front movable wall and
the rear end of the rear chamber is sealed
by means of a rear movable wall. Furthermore,
in the container wall there is arranged an
overflow passage which can connect the front
and the rear chambers.
In a storage position before the injection,
there is no communication between the front
and the rear chambers. The inlet as well
as the outlet of the overflow passage ends
in the front chamber.
When the container is to be readied for injection,
the rear, movable wall in the rear chamber
is moved forwards, and due to the incompressibility
of the liquid, the front movable wall will
then also be moved forwards until it reaches
a position just opposite the overflow passage
in the wall of the container. When the rear
movable wall thereafter is moved further
forwards, the liquid will be pressed through
the overflow passage into the front chamber
where it will be brought into contact with
the medicament substance and dissolve this.
At the injection the two walls will act together
as a piston and press the prepared injection
solution out through a cannula introduced
through the front end wall in the front chamber.
In certain cases the medicament substance
can be so sensitive that special measures
must be taken to protect the substance against
mechanical influence at the time af dissolution
as well as in the further handling of the
solution. This applies for example to freeze-dried
growth hormones where even a simple shaking
of the substance and the liquid can lead
to a non-acceptable biochemical change. The
readying of the container for injection must
then be made with the utmost carefulness.
It would be very desirable to have available
an injection device that is as easy to bring
along and handle as those previously known
for simple cylinder ampoules in which the
medicament substance is present in a liquid
state as a solution, suspension or emulsion,
at the same time as the advantages of mixing
containers at injecticn of sensitive substances
might be utilized. This object is now achieved
by the present invention.
According to the invention there are provided
a method and a device for preparation of
an injection solution of one or more substances
sensitive to degradation, and a subsequent
injection of this solution.
It is intended by the method of the invention
to prepare a solution, emulsion or suspension
in water of one or more sensitive medicament
substances for one or more subsequent injections,
using a multi-chamber cylinder ampoule known
per se which comprises a front space containing
the sensitive medicament substance and is
sealed at its front end by means of a membrane
penetrable to an injection cannula and delimited
at its rear end by a front movable wall,
a rear space containing an aqueous phase,
and which is delimited at its front end by
the front movable wall and is delimited at
its rear end by a rear movable wall, and
an overflow passage arranged in the wall
of the ampoule between the rear and the front
space, the rear movable wall being moved
forwards and entraining thereby the aqueous
phase and the front, movable wall until this
is just opposite the overflow passage so
that the aqueous phase upon continued forward
motion of the rear movable wall will flow
past the front movable wall into the front
space and dissolve, emulsify or suspend the
medicament substance. What characterizes
the method is that the aqueous phase is made
to flow calmly from below and upwards through
the medicament substance avoiding any shaking
and admixture of air.
Moreover, the invention comprises a device
for carrying out the present method. What
characterizes the device is that it comprises
a)a container for the constituents of the
injection solution, in which the constituents
are kept separated but can be brought together
by external action to be mixed and dissolved
and which is made as a tube which is sealed
at its front end by means of a penetrable
membrane, contains in a space between the
penetrable wall and a front movable wall
the solid constituents of the injectian solution,
contains in a space between the front movable
wall and a rear movable wall the liquid constituents
of the injection solution and is provided
in the tubular wall with an overflow passage
so arranged that when the rear movable wall
is moved forwards together with the liquid
and the front movable wall, the liquid can
flow past the front movable wall and be mixed
with the solid constituents to a solution;
b)holder means in which the container can
be fixed such that the constituents of the
injection solution are brought together and
mixed and which is made of two tubular members
which can be screwed together and enclose
the container so that when the members are
screwed together the front end of the container
with the penetrable membrane is exposed at
the front end of the holder means to be penetrated
by an injection cannula and the rear movable
wall at the rear end of the container is
moved forwards together with the liquid and
the front movable wall so that the liquid
is made to flow through the overflow passage
over to the space of the solid constituents
to be mixed with these to a solution;
c)holder means for an injection cannula
arranged to be applied to the front end of
the holder means of the container so that
the cannula can be connected with the interior
of the container through the penetrable membrane;
and
d)a dosing device connected to the holder
means of the container, through the operation
of which the rear movable wall in the container
is made to be displaced forwards in a controlled
way administering determined doses of the
injection solution, said dosage device being
brought to a starting position for dosage
when the holder means of the container is
screwed together.
In the following, the invention is described
in greater detail with reference to the accompanying
drawing.
An embodiment of a device according to the
invention is shown in the drawing. Fig. 1 in the drawing shows a dual-chamber cylinder
ampoule having two chambers for use in an
injecticn device. Fig. 2 is a general view of an injection device
according to the invention and Fig. 3 shows the same device in its disassembled
state. Fig. 4 is a sectional view of the device in its
disassembled state and Fig. 5 shows the device ready for injection.
A sectional view of a dual-chamber cylinder
ampoule for use in an injection device according
to the invention is shown in Fig. 1. The
ampoule consists of a tube 1, preferably
of glass or a plastic material, which is
formed as a bottle-neck with a flange 2 at
its front end. The front end is sealed by
means of a membrane 3 of rubber or a suitable
plastic material which is secured by means
of a metal capsule 4. The capsule 4 has an
aperture 5 at its central portion so that
the membrane 3 is uncovered there. The edge
portion of the capsule is further bent around
the flange 2 so that the membrane 3 is secured
against the front aperture of the ampoule.
The ampoule is divided into a front space
6 and a rear space 7 by means of a movable
partition 8. The rear end of the ampoule
is sealed by the movable wall 9 which, thus,
also seals the rear chamber 7. The two movable
walls 8 and 9 can be moved forwards in the
ampoule with sealing against the ampoule
wall, said ampoule having a substantially
circular-cylindrical shape for this purpose.
The front chamber 6 of the ampoule contains
one or more medicament substances 10 in dry
state, preferably freeze-dried. In this form,
also sensitive substances have a relatively
good stability. The rear chamber 7 contains
a liquid phase 11 which is intended to dissolve
the dry injection substance. This liquid
phase usually consists of water or a physiological
saline solution, and such auxiliary substances
as are usual in pharmacological practice
can be added to it.
In the wall of the ampoule, an overflow passage
12 in the form of a recess is arranged and
extends substantially in the longitudinal
direction of the ampoule. The overflow passage
12 is located such that it is completely
in the front space 6 before the ampoule has
been readied for injection and has such a
length that it enables a flow past the movable
wall 8.
Fig. 2 shows the injection device of the
invention in an assembled state where it
can be easily carried along by the patient.
The device is generally shaped as a fountain-pen
and consists of a front casing portion 13
which encloses a dual-chamber cylinder ampoule
according to Fig. 1 for the agent to be injected,
a rear casing portion 14 enclosing a mechanism
for dosage and administration of the agent
and a protective cap 15 over the injection
cannula. The mechanism for dosing and administering
the agent is made in any one of several ways
known per se and is not described here in
greater detail. Usually it works in such
a way that the control knob 16 at the rear
end of the device is turned so that an index
is set against a scale, a suitable dose being
determined. In administration, the control
knob is thereafter pushed in, whereby the
set dose is administered through the cannula.
Many different embodiments of such a mechanism
for dosage and administration are previously
known and can be used in the injection device
of the present invention.
Fig. 3 shows the injection device in its
disassembled state. Here the protective cap
15 has also been removed so that the front
portion 17 of the cannula with its holder
means 18 is shown. The cannula can be screwed
onto the front end of the front casing portion
13 by means of the holder device and can
be easily replaced. The protective cap 15
should then be applied all the time so that
sterility is maintained, and should not be
removed until immediately before the injection.
An aperture 19 is also made in the front
casing portion 13 through which the user
can easily control whether any ampaule is
inserted and how much is left of the injection
solution.
The rear casing portion 14 can be screwed
into the front casing portion 13 by means
of the thread 20. Simultaneously with this
screwing an inserted dual-chamber cylinder
ampoule for injection is readied, as will
be described more closely in the following.
Fig. 4 is a view partly in longitudinal section
of the disassembled injection device according
to Fig. 3. Here it is apparent that a dual-chamber
cylinder ampoule of the type shown in Fig.
1 has been inserted into the front case portion
13 and moved so far that its membrane 3 has
been uncovered to be penetrated by the cannula.
In the rear case portion 14 the dosage and
administration mechanism is schematically
indicated at 22. This mechanism is provided
with a forwardly directed operating rod 23.
By its actuation the dual-chamber cylinder
ampoule is first readied for injection and
determined doses of the injection agent can
thereafter be administered by the aid of
the control knob 16.
The rear casing portion 14 can be screwed
into the front casing portion 13 by the external
thread 20 engaging the internal thread 24.
Fig. 5 shows the device assembled and ready
for injection. Here the rear movable wall
9 has been moved so far that it has got into
contact with the front movable wall 8. This
has been brought so far that it has got just
opposite the overflow passage 12 and the
liquid phase 11 has then flowed past the
front movable wall 8 and been mixed with
the dry medicament substance. The pointed
rear end 21 of the cannula has also been
introduced through the membrane 3. The two
movable walls 8 and 9 are in contact with
each other and have been moved so far that
all air in the front space 6 has been expelled
through the cannula. The device is now ready
for injection.
The function of the device when being readied
for injection is as follows:
In the rear casing portion 14, the operating
rod 23 and the control knob 16 of the dosing
and administering mechanism 22 are first
set to a starting or zero position. This
is done in a way as determined by the design
of the used mechanism known per se. The rear
casing portion 14 is thereafter screwed into
the front casing portion 13 until the operating
rod 23 is resting lightly against the rear
movable wall 9 in the dual-chamber cylinder
ampoule.
When the rear casing portion is screwed in
further, the operating rod will press the
rear movable wall 9 forwards in the cylinder
ampoule, and as the liquid 11 in the rear
space 7 is substantially incompressible,
the front movable wall 8 will also be pressed
forwards. A certain overpressure in the front
chamber 6 will arise as air cannot escape.
When the front movable wall 8 has been pressed
so far that it is just opposite the overflow
passage 12 a liquid connection will be established
between the front and the rear chambers.
By the further forward motion of the rear
movable wall 9 the liquid 11 will then be
urged into the front chamber 6 through the
overflow passage 12. At this stage, the front
movable wall 8 will not move.
When all liquid has been urged into the front
space, the rear movable wall 9 will get into
mechanical contact with the front movable
wall 8. The liquid will now dissolve the
dry medicament substance 10 forming an injection
solution ready for use. The holder 18 with
the attached cannula 17 is thereafter screwed
onto the front casing portion 13, the membrane
3 of the cylinder ampoule being pernetrated
by the rear cannula tip 21, and the overpressure
in the front chamber is released.
By pushing the control knob 16 fully home,
the operating rod 23 is actuated so that
the walls 9 and 8 are moved further forwards
and air in the cylinder ampoule will exit
through the cannula 17. The device is now
ready for injection, as shown in Fig. 5.
When readying the device it is necessary
to hold it vertically with the cannula end
pointing upwards, and the screwing together
must not be carried out too quickly. In this
way the liquid will rise calmly through the
dry substance dissolving it, and no vigorous
mixing takes place. Such vigorous mixing
is unsuitable for many sensitive substances
as it may affect the substance.
It is a preferred embodiment that the dual-chamber
cylinder ampoule 1 is positioned in the front
casing portion 13 and the solid medicament
is dissolved before the cannula 21 is brought
through the membrane 3 of the ampoule. By
the overpressure occurring, the tendency
to foaming and formation of bubbles is reduced
when the liquid and the solid material are
mixed, which is less harmful to the medicament
substance. However, for medicament substances
that are not so sensitive, the cannula holder
18 with the cannula can be screwed onto the
front casing portion 13 before the cylinder
ampoule is introduced and the two casing
portions are screwed together. The rear tip
of the cannula will then penetrate the membrane
3 before the solid substance and the liquid
are mixed and no overpressure arises in the
mixing chamber.
When the device is to be used for the administration
of an injection the protective cap over the
cannula is first taken off. The desired dose
is thereafter set by means of the control
knob 16 and by depressing the control knob
the dose is administered through the cannula.
Further doses can thereafter be administered
as long as there is injection solution left
in the cylinder ampoule. After each administration,
the cannula is usually replaced with a new
sterile cannula. This can easily be done
by screwing off the holder device 18 with
the attached cannula from the front end of
the injection device and a new holder device
with cannula is screwed on. At the same time
the rear pointed end of the cannula will
penetrate the membrane 3 and provide a liquid
connection to the interior of the ampoule.
The device of the invention is preferably
used for subcutaneous injection but other
injection methods according to current medical
practice are also possible, for example intramuscular
injection.
When the cylinder ampoule is emptied, the
injection device is screwed apart and the
empty ampoule is taken out. The dosing mechanism
is set to zero and after this the device
can be readied again for injection, as indicated
above. The screwed-together and readied device
can be easily carried along by the user in
order to be used at suitable times.
It may be necessary to protect sensitive
medicament substances, especially of the
polypeptide type, against mechanical action
when they are in a dissolved form. The moments
especially critical are the very reconstitution
of a dried powder, on one hand, and, on the
other hand, the subsequent handling of the
prepared solution. The latter will be particularly
important when multi-dose preparations are
concerned, which must necessarily be handled
a number of times.
The use of conventional packages and hypodermic
syringes does not give any aid per se to
protect against mechanical stresses which,
however, this invention does. As the reconstitution
of the dried powder by means of the invention
is carried out in a very careful way determined
by the design, the sensitive medicament substance
is spared. As the solution is prepared at
a certain overpressure, foaming and formation
of bubbles are also prevented at this stage.
The subsequent handling of the prepared solution
will also be very gentle in the invention.
Practically all air that has been in contact
with the solutian is removed as the injecting
device is readied to give off a first injection
from a newly inserted dual-chamber cylinder
ampoule. In this way the interface is eliminated
which in the handling of the container with
solution gives rise to the negative effects
on the sensitive medicament substance, and
the container can thereafter be handled without
special respect to the sensitive nature of
the solution.
Thus, it is possible by the present invention
to prepare a solution to be used for a long
or short time in a gentle way and to transport
a prepared solution without degrading the
quality of the sensitive medicament substance
due to mechanical stress. Therefore the invention
makes it possible that also sensitive medicaments
can be made available for a comfortable ambulatory
treatment. The medicament substances that
can be used in the present device can consist
of any substance or mixture of substances
used in the previously known dual-chamber
ampoules or which are suitable for this use.
However, sensitive substances that cannot
be stored for a long time in solution and
which also have a tendency to be altered
when dissolved are especially suitable. Examples
of such substances are various polypeptides
such as hormones and interferon. The invention
has been found to be particularly suitable
in the preparation and injection of solutions
of growth hormones. These are very sensitive
and are easily modified when a solution of
them is prepared. By using the present invention
in this case, such an influence is considerably
reduced. This is extremely surprising and
not predictable by one skilled in the art.
The dry medicament substances are usually
present in a freeze-dried or lyophilized
state before the preparation of the injection
solution. The liquid used for the solution
usually consists of water to which agents
for adjusting the osmotic pressure, preservatives,
etc. have often been added in accordance
with current pharmacological practice. It
is also possible that the liquid phase itself
can contain dissolved substances having a
pharmacological effect which is then exerted
together with the effect of the agent that
is later dissolved in the liquid.
Another embodiment is that the liquid can
consist of an injectable fat emulsion, for
example such a one as is described in US
patents 4 073 943 and 4 168 308. In this
case the dry injection substance contains
a water-soluble or hydrophilic agent which
is dissolved or dispersed in the aqueous
phase of the emulsion in the mixture.
The injection device is made of some suitable
material such as metal, for example stainless
steel or light metal or some suitable plastic
material. The choice of material is well
within the competence of one skilled in the
art.
Moreover, it should be noted that the method
and device of the invention shown in the
drawing and the detailed description are
only an example and that other embodiments
are also possible within the scope of the
claims.
---------------------
CLAIMS
1. A method of preparing a solution, emulsion
or suspension in water of one or more sensitive
medicament substances for one or more subsequent
injections using a multi-chamber cylinder
ampoule(1)known per se and camprising a front
space(6)containing the sensitive medicament(10)and
sealed at its front end by means of a membrane(3)penetrable
to an injection cannula(17)and delimited
at its rear end by a front movable wall(8),
a rear space(7)containing an aqueous phase(11)and
delimited at its front end by the front movable
wall(8)and delimited at its rear end by a
rear movable wall(9), and an overflow passage(12)arranged
in the wall of the ampoule between the rear
and the front spaces, said rear movable wall(9)being
moved forwards and entraining thereby the
aqueous phase(11)and the fronts, movable
wall(8)until this is just opposite the overflow
passage(12), so that the aqueous phase(11)upon
continued displacement of the rear movable
wall(9)will flow past the front movable wall
into the front space and dissolve, suspend
or emulsify the medicament substance (10), c
h a r a c t e r i z e d in that the aqueous
phase(11)is made to flow calmly from below
and upwards through the medicament substance(10)avoiding
any shaking and admixture of air.
2. The method of claim 1, c h a r a c t
e r i z e d in that the aqueous phase(11)and
the medicament substance(10)are brought into
contact with one another at a pressure above
atmospheric.
3. The method of claim 1 or 2, c h a r a
c t e r i z e d in that the injection cannula(17)is
made to penetrate the membrane(13)only after
the medicament(10)has been dissolved, emulsified
or suspended in the aqueous phase(11)
4. A device for the preparation of an injection
solution of degradation-sensitive substances
and a subsequent injection of this solution, c
h a r a c t e r i z e d in that it comprises
a)a container(1)for the constituents of the
injection solution, in which the constituents
are kept separated but can be brought together
by external action to be mixed and dissolved
and which is made as a tube(1)which is sealed
at its front end by means of a penetrable
membrane(3), contains in a space(6)between
the penetrable membrane and a front movable
wall(8)the solid constituents(10)of the injection
solution, contains in a space(7)between the
front movable wall(8)and a rear movable wall(9)the
liquid constituents(11)of the injection solution
and is provided in the tubular wall with
an overflow passage(12)so arranged that when
the rear movable wall(9)is moved forwards
together with the liquid(11)and the front
movable wall(8), the liquid can flow past
the front movable wall(8)and be mixed with
the solid constituents(10)to a solution;
b)a holder means in which the container(1)can
be fixed such that the constituents of the
injection solution are brought together and
mixed and which is made of two tubular members(13,
15)which can be screwed together and enclose
the container(1)such that when the members
are screwed together the front end of the
container with the penetrable membrane (3)is
exposed at the front end of the holder means
to be penetrated by an injection cannula(17,
21)and at the rear end of the container,
the rear movable wall(9)is moved forwards
together with the liquid(11)and the front
movable wall(8)so that the liquid(11)is made
to flow through the overflow passage(12)over
to the space of the solid constituents(5)to
be mixed with these to a solution;
c)a holder means(18)for an injection cannula(17)arranged
to be applied to the front end of the holder
means(13)of the container so that the cannula(21)can
be connected with the interior(6)of the container
through the penetrable membrane(3); and
d)a dosing device(27)connected to the holder
means(14)of the container, through the operation
of which the rear movable wall(9)in the container
is made to be displaced forwards in a controlled
way administering determined doses of the
injection solution, said dosage device(22)being
brought to a starting position for dosage
when screwed together with the holder means(13,
14)of the container.
ABSTRACT
The invention relates to a method and a device
for the preparation of a solution, emulsion
or suspension of a sensitive medicament substance
in an aqueous medium and a following injection
thereof.
In the method of the invention, a dual-chamber
cylinder ampoule(1)known per se is used for
the mixture of the aqueous medium(11)and
the medicament(10), the aqueous medium(11)being
made to flow calmly from below and upwards
through the medicament substance(10)in order
to avoid any shaking and admixture of air.
The mixing is preferably carried out at a
pressure above atmospheric.
Moreover, the invention relates to an injection
device for the preparation of an injection
solution and a following injection of said
solution. Said device comprises a front member(13)enclosing
a dual-chamber cylinder (1), in which the
dry medicament substance(10)is separated
from a liquid phase(11), and a rear member(14)enclosing
a dosing and administering mechanism(22).
When the two members are screwed together
the liquid phase(11)will be mixed with the
dry medicament substance(10)and dissolve
it, and the finished solution can thereafter
be injected by means of the dosage and administration
mechanism(22)through a cannula(17)arranged
at the front end of the front member(13).
The invention will enable for medicament
substances sensitive to mechanical influence
that the mixture of the dry substance and
the aqueous medium as well as the following
handling of the prepared agent can be carried
out so gently that a deterioration of the
quality of the medicament through mechanical
influence is minimized.
(Fig. 4)
乙第２８号証の１抄訳
（冒頭ページ）
日付 １９８８年６月１６日
出願人 カビビトゥルムＡＢ，ストックホルム，スェーデン
ＥＰ８８ ８５ ０２３５．８
０ ２９８０６７
出願番号 ８７０２７３５−５
出願日 １９８７年７月２日
国際分類 Ａ６１Ｍ
発明の名称 注射方法及び注射装置
本書に添付した書類は、欄外記載の日にスェーデン特許庁に出願された発明の説明、クレーム及び図面の真正なコピーであることを証明する。
カール クリンバーグ
アンヌ マイ マルムステン
（発明の説明（英文）７ページ３８行〜８ページ１行）
「注射装置を準備するとき、注射針の先端は上向きに垂直に保持されていなければならず、かつ、ねじ込みはあまりに早く実施してはならない。このようにして、水性相は乾燥物質を通して静かに上昇して物質を溶解し、活発な混合は起こらない。活発な混合は、物質に影響を及ぼすため、多くの敏感な物質にとっては不適合である。」
（同１１ページ「クレーム１」）
一回またはそれ以上の注射を行うために、それ自体公知の多室シリンダアンプル（１）を使用して、一種またはそれ以上の敏感な薬剤の水溶液、エマルジョンまたは水懸濁液を調製する方法であって、該アンプルは、敏感な薬剤（１０）を収納し前端が注射針（１７）により貫通可能な膜手段（３）によりシールされ後端が前部可動壁（８）により規制された前側スペース（６）、及び、水性相（１１）を収納し前端が前側可動壁（８）により規制され後端が後側可動壁（９）で規制された後側スペース（７）により構成され、後側スペースと前側スペースの間のアンプルの壁面に設けられた溢流通路（１２）を備え、前記後側可動壁（９）が前方に移動して水性相（１１）と前側可動壁（８）を溢流通路（１２）と対抗する位置まで移送し、もって、後部可動壁（９）の連続した移動により水性相（１１）が前側可動壁を通って前側スペースに流入して、薬剤（１０）を溶解し、懸濁しまたは乳化する方法において、
水性相（１１）を、振盪または空気の混入を防止しつつ、薬剤（１０）を通して下側から上側に静かに流通させるようにしたことを特徴とする方法。
