[0001] This invention relates to an improved method of mixing two substances using a compartmented
vial and in particular it relates to an improvement using a compartmented vial capable
of holding two substances, in particular medicaments, separately in two compartments
until required for an injection, for example, wherein the two substances are then
required to be mixed in the vial before use.
[0002] Medicaments used in injections are generally classified into powdered forms, freeze-dried
forms, liquid forms etc. The vessels available for storing such medicaments include
glass or plastic ampoules and vials. At the present time, glass vessels have widely
been used. A powdered or freeze-dried medicament is generally dissolved by adding
to it a dissolving fluid stored in another vessel, possibly by means of a syringe.
In the case of liquid medicaments, a liquid medicament in one vessel may be injected
into another vessel containing another liquid medicament, resulting in the mixing
of the two liquids. However, such operations wherein means, such as syringes, are
required, to transport a liquid from one vessel to another can give rise to mishaps.
[0003] A vessel has been proposed in which two different types of medicaments, for example
a main ingredient and a dissolving fluid, are stored in two separate compartments
of a single vessel, divided by a partition wall. In use, this partition wall can be
removed to allow the two medicaments to mix. Such a vessel has already been used in
Europe as a means for preventing mishaps.
[0004] The following methods (I) and (II) are generally used to remove the partition wall:
Method (I)
[0005] Referring to Fig. 4, two medicaments, for example a liquid medicament 6 and a solid
medicament 7, are separately stored in an upper compartment A and a lower compartment
B of a container 1. The compartments A, B are separated by an intermediate plug 2.
The vial 1 has a mouth which is sealed by a rubber stopper 3′ comprising a cap E′
and a body F′ protruding from a lower side of the cap E′. The body F′ is longer than
that of an ordinary stopper for a vial such that an upper part of body still protrudes
from the mouth C of the vial 1 when it has been sealed. To aid needle piercing, the
stopper 3′ contains a narrow recess D′. An end of the body F′ furthest from the cap
E′ has a greater circumference than the end of the body F′ adjacent the cap E′. Only
the lower end of the body of the stopper is inserted into the mouth C of the container
1 to seal it. The part of the rubber stopper 3′ in contact with the mouth C is fastened
by an aluminum cap 4′ in such a manner that the rubber stopper 3′ projects out from
the mouth C, and the alumunium cap 4′ and the protruding part of the rubber stopper
3′ are further covered by an over cap 5′ made of a plastics material. In use, this
over cap 5′ is removed and the stopper 3′ is manually pushed downwards (see Fig. 5),
thus raising the pressure in compartment A which eventually displaces the intermediate
plug 2 allowing communication between the two compartments A and B (US patent Nos.
4,089,432, 4,180,173, 4,274,543).
Method (II)
[0006] As described in Japanese Patent Publication No. 39227/186, a rod is fitted to the
lower side of a rubber stopper and in use the rod is pushed downwards to force the
intermediate plug out of position, thereby allowing the two medicaments to mix.
[0007] Method (II) is hard to put to practical use, since the shape of the rubber stopper
is extremely complicated and therefore both difficult and expensive to manufacture
in order that the rod can be operated successfully. Furthermore inserting a syringe
needle into such a stopper is not easy.
[0008] On the other hand, Method (I) has now been put to practical use because of the simplicity
of the shape of the rubber stopper and the intermediate plug. However, Method (I)
has the disadvantage that, as shown in Fig. 4 and Fig. 5, the recess D′ of the rubber
stopper 3′ is so narrow that when a syringe needle pierces the rubber stopper 3′ there
is a danger that the inner wall of the body of the rubber stopper is scraped thus
generating rubber scraps. Such rubber scraps tend to clog the needle such that it
does not function. Therefore, needle piercing needs to be carried out with great care
in such a manner that the stopper is pierced vertically. However, as it is impossible
to check what is actually happening inside the stopper, this is often not easy to
do.
[0009] A further problem is that in order that the intermediate plug is caused to be displaced
and falls into compartment B, a force higher than the resistance to movement of the
intermediate plug 2 is required, as represented by the following formula (1): (Manual
Thrusting Force Value - Sliding Resistance Value of Rubber Stopper Movement Resistance
Value of Intermediate Plug) (1)M When the rubber stopper C is pushed downwards
by a strong force as shown in Fig. 5, the rubber stopper itself tends to distort because
of the unsupported length protruding from the vial thus making it difficult to handle.
[0010] Another problem arising herein is the sliding resistance value of the rubber stopper
3′. The primary function required of a rubber stopper 3′ is that it efficiently seals
the vial container 1 and the secondary function is that it slides into a sealing position
when pushed into the vial container 1. Since these primary and secondary functions
are effected at the same time contradictory conditions are simultaneously required.
On one hand, the gap between the inner surface of the mouth of the vial and the outer
surface of the stopper body is required to be minimised such that the inner diameter
of the vial is actually less than the rubber stopper diameter, so as to maximise the
sealing quality. On the other hand, in order to ease insertion of the stopper into
the vial mouth, the gap is required to be maximised. Therefore, the sliding resistance
value of the rubber stopper 3′ itself should be approximately equal to the movement
resistance value of the intermediate plug 2. When the right term is transposed in
the formula (1), the following relationship is given:
Manual Thrusting Force Value > Movement Resistance Value of Intermediate Plug + Sliding
Resistance Value of Rubber Stopper
Thus, the sliding resistance value of the rubber stopper 3′ is the smaller, the manual
thrusting force is the smaller and accordingly, handling of the compartmented vial
is improved.
[0011] It is an object of the present invention to provide an improved method of utilising
a compartmented vial in which two substances, such as a lyophilized medication and
a solvent, can be held in complete independence from each other until it becomes desirable
to mix them before use.
[0012] According to the invention, there is provided a method of storing and mixing substances
for use in an injection comprising the steps of (i) placing the substances separately
in an upper and a lower compartment (A, B) of a compartmented vial container, in which
the two compartments are joined by a neck portion having a smaller internal diameter
than that of the compartments, in which neck portion is positioned a displaceable
plug to separate and seal the compartments from each other, (ii) sealing the container
with a stopper positioned in a mouth opening at an end of the upper chamber away from
the neck portion said mouth opening having a larger internal diameter than of said
neck, (iii) displacing the plug from the neck portion to allow the substances in the
two compartments to combine to form a mixture, characterised in that the plug is displaced
by injecting air with a syringe through the stopper into the upper compartment to
raise the pressure in the upper compartment such that the plug is forced downwards
out of the neck into the lower compartment.
[0013] A preferred embodiment of the invention will now be described by way of reference
to the accompanying drawings, in which:
Fig. 1 is a sectional view of a compartmented vial, showing a medication and a solvent
held in complete independence;
Fig. 2 is a schematic view showing the compartmented vial of Fig. 1 in use.
Fig. 3 is a sectional view of an alternative embodiment of a compartmented vial;
Fig. 4 is a sectional view of a compartmented vial according to the prior art;
Fig. 5 is a schematic view showing the vial of Fig. 4 in use.
[0014] Referring to Fig. 1, a vial 1 has two compartments A and B which are separated by
a displaceable intermediate plug 2 such that medicaments 6 and 7 may be stored completely
independent from each other. Vial 1 has an open mouth C which can be sealed by inserting
a rubber stopper 3 of a known type. The stopper 3 has a wide recess D beneath a designated
needle piercing area. The stopper 3 has a head portion E, a part of the lower surface
of which seals against mouth C of the vial 1. The stopper 3 also has a body portion
F protruding from the lower surface of the head portion E, which, in use, is inserted
into the mouth C of the vial 1, and which closely contacts the inner surface of the
mouth C of vial 1. The rubber stopper 3 isfastened in position to the vial 1 by a
flip-off aluminum cap 4. A flip-off plastic cover is fitted over the aluminium cap
4. Joining the compartment A and B is a constricted neck having an internal diameter
less than the mouth C of vial 1. After charging compartment B with the required medicament,
intermediate plug 2 is inserted into the neck. Compartment A can then be charged with
another medicament and the rubber stopper 3 is fixed in the mouth C of the vial 1
as shown in Fig. 1.
[0015] In use, a syringe needle 8 pierces the rubber stopper 3 as shown in Fig. 2 into recess
D and air contained in the body 9 of the syringe is forced into compartment A by depressing
plunger 10. This results in an increase in the internal pressure in compartment A,
which forces displacement of the intermediate plug 2 out of the neck and into compartment
B, allowing communication between compartments A and B and thus the mixing of the
two medicaments 6 and 7. In the aforementioned example medicament 6 is dissolved in
a solvent 7 to form a liquid medicament which is then taken up into the syringe.
[0016] Operation of the vial container is ordinarily carried out by introducing air into
the vial 1 of an amount at least corresponding to that to be taken into the syringe,
the liquid medicament being sucked into the body of the syringe assisted by this pressurization.
Otherwise, the pressure in the vial 1 is negative whilst charging the syringe which
makes operations difficult.
[0017] According to the method of the present invention, therefore, it is possible to effect
a syringe charging operation by the same procedure as the mixing operation and moreover,
the fear of scraping the inner wall of the body portion of the stopper during insertion
of the needle is removed as the rubber stopper is fixed in position and the recess
D in the body portion is of a broad diameter. As illustrated above, mixing in the
vial can be effected only by depressing the plunger of a syringe and then raising
the plunger for the purpose of charging without the necessity of manual thrusting
or pressing the rubber stopper, so a safety system which can be easily handled and
without any mis-haps is available.
[0018] Only the one embodiment of the present invention is used in the foregoing illustration
and the following examples, but the present invention is not intended to be limited
thereto and does include all embodiments of the method utilising a vial container
body comprising two compartments A and B, an intermediate plug disposed in a constricted
neck between the compartments A and B and a rubber stopper closely fixed to the upper
compartment A. Another embodiment of the vial 1 is shown in Fig. 3.
[0019] The following examples are given in order to illustrate the present invention in
detail without limiting the same.
Examples
Examples 1 to 4 and Comparative Examples I and 2
[0020] Using the embodiment of the vial container as shown in Fig. 1 and Fig. 2 having the
dimensions shown in Table l, various tests (Examples 1 to 4) were carried out to examine
the following:
(1) the force required to displace the intermediate plug.
(2) the needle piercing operation.
(3) the occurence of needle piercing fragments, and
(4) moisture permeability in the compartment B.
[0021] For comparison, similar tests were carried out using the vial and rubber stopper
of the prior art, as shown in Fig. 4 and Fig. 5 (Comparative Examples 1 and 2). In
these examples, as the intermediate plug, there was used a same sample consisting
of a same rubber material subjected to a same surface treatment. The test methods
are illustrated below and the test results are given in Table 1 see page 11):
(1) Force required for movement of intermediate plug
[0022] In Examples 1 to 4, the pressure in compartment A was measured when the needle of
a syringe, in which the plunger had been set to a maximum scale mark, pierced the
piercing area of the rubber stoppersample 3, and the plunger depressed gradually by
means of a push-pull gauge (made by Imamura Seisakusho Co.) to feed air into the upper
compartment A until the intermediate plug 2 was displaced from the neck of vial A
into the lower compartment B.
[0023] In Comparative Examples 1 and 2, the pressure was measured when the rubber stopper
3′ was gradually pushed into the vial 1 by means of a push-pull gauge until the intermediate
plug was displaced into lower compartment B.
(2) Needle piercing operation
[0024] Comparison of these samples was carried out by the actual operations as to the degree
of difficulty for visually checking the position of the needle point during the piercing
operation and the degree of difficulty in charging the syringe with a liquid medicament
in the vial.
(3) Needle piercing fragments
[0025] According to the fragment test of BS (British Standard) 3263 (1960), the number of
fragments occurring and falling from the stopper during the piercing operation were
counted (rubber fragments/100 times).
(4) Moisture permeability in compartment B
[0026] After drying the vial container, 0.4 ± 0.05 g

of dried calcium chloride was placed in the lower compartment B, the intermediate
plug 2 inserted into the constricted neck between compartments A and B, 5 ml of water
placed in the upper compartment A and the vial 1 sealed with the rubber stopper 3
or 3′, which has fastened to the vial by means of aluminum cap 5 or 5′, thus obtaining
a sample body.
[0027] The sample body was held at 40°C for 4 weeks, after which the rubber stopper and
the water in the upper compartment A were removed and dried at 90°C for 1 hour. The
intermediate plug was then forced to be displaced into compartment B and 5 ml of alcohol
added to the contents of compartment B to adequately dissolve the calcium chloride
thus preparing a solution, 50 µl of which was taken as a sample and subjected to measurement
of the amount of water therein using a Karl Fischer's meter. The permeability ratio
was calculated by the following formula (2):

A sample giving 0% by the above described formula (2) was estimated as "good".
[0028] It will be apparent from the results of Table 1 that in the vial used in Examples
1 to 4, the force required to displace the intermediate plug into compartment B is
in the range of 3.51 to 6.90 kg which is less than in the case of the prior art vials,
which is in the range of 7.85 to 11.3 kg (comparative Examples 1 and 2). The needle
piercing fragments scarcely occurred in samples 1 to 4 as compared with the prior
art Examples which showed fragments of 24/100 to 36/100 times. Furthermore, the vial
samples 1 to 4 showed a very simple and easy piercing operation. As to the permeability
of water into compartment B, both the samples 1 to 4 and comparative Examples 1 and
2 showed good results.
[0029] The advantages of the method using the compartmented vial container according to
the present invention over the prior art can therefore be summarized as follows:
(1) Since the compartmented vial container used in the method of the present invention
utilises a known rubber stopper in place of the special slidable rubber stopper of
the prior art, operation for use is simplified, said operation comprising the steps
of removal of the intermediate plug by feeding air into the upper compartment A using
the same syringe, preferably, which is to be used for injecting the medicament stored
in the vial container, allowing the two medicaments to be mixed and charging the syringe
with the resulting mixure.
(2) The needle piercing operation is largely improved due to the small force required
for the displacement of the intermediate plug, easy visual checking of the needle
piercing operation and use of a large needle piercing area in the rubber stopper which
also results in the highly reduced occurrence of needle piercing fragments.
(3) The compartmented vial of the prior art is subject to contamination of the needle
piercing area as the operator's thumb presses down on this area when forcing the stopper
into the vial mouth. In the improved method this problem is resolved as no such thumb-pressing
operation is required, only the ordinary injecting operation.
(4) For application of a medicament, the occurrence of mishaps is reduced to a minimum.
(5) Use of a rubber stopper of the ordinary known type instead of the special rubber
stopper of the slidable type described in the prior art vials, results in reduction
of the production cost of the compartmented vial used in this method described.
1. According to the invention, there is provided a method of storing and mixing substances
(6, 7) for use in an injection comprising the steps of (i) placing the substances
separately in an upper and a lower compartment (A, B) of a compartmented vial container
(1), in which the two compartments are joined by a neck portion having a smaller internal
diameter than that of the compartments, in which neck portion is positioned a displaceable
plug (2) to separate and seal the compartments from each other for storage, (ii) sealing
the container with a stopper (3) positioned in a mouth opening (C) at an end of the
upper compartment away from the neck portion said mouth opening having a larger internal
diameter than of said neck, (iii) displacing the plug from the neck portion to allow
the substances in the two compartments to combine to form a mixture, characterised
in that the plug is displaced by injecting air with a syringe (8, 9, 10) through the
stopper into the upper compartment to raise the pressure in the upper compartment
such that the plug is forced downwards out of the neck into the lower chamber.
2. A method of mixing substances (6, 7) for use in an injection as claimed in claim
1 in which the syringe (8, 9, 10) is charged with the resulting mixture.
3. A compartmented vial container for use in the method of claim 1 or claim 2 comprising
a vial body (1) having an upper compartment (A) having a mouth opening (C) at an upper
end thereof and a lower compartment (B) communicating with a lower end of said upper
compartment by means of a neck portion having a smaller internal diameter than that
of the mouth opening, a plug (2) being positioned in the neck portion to separate
and seal the upper and lower compartments from each other until forcibly removed,
a stopper (3) having a head (E) and a body (F), the body protruding from a lower surface
of the head and being positioned in the mouth opening of the vial to seal the upper
compartment from the atmosphere in which the stopper is adapted to form a seal around
a needle of a syringe after penetration of the stopper by said needle.
4. A compartmented vial container as claimed in claim 3 in which the body (F) of said
stopper (3) contains a wide recess (D).
5. A two-compartment vial container comprising a vial body (1) consisting of an upper
compartment (A) having an upward opening end (C), a cylindrical constricted connection
part disposed under the upper compartment and having a smaller inside diameter than
that of the opening end and a lower compartment (B) having no opening part except
a part communicating with the constricted connection part, an intermediate displaceable
plug (2) inserted into the constricted connection part when medicaments (6, 7) are
held and stored, a rubber stopper (3) consisting of a cap or head part (E) and a body
part (F) and fixed to the upward opening end such that the cap part contacts closely
with the upper flange of the opening end of the vial body and the body part is inserted
into the vial container and an aluminium cap (4) for covering the cap part of the
rubber stopper and the outer circumference of the opening end of the vial body, in
which the intermediate displaceable plug is displaced by piercing a central portion
of the rubber stopper with an injection needle (8) and feeding air into the upper
compartment to impart a pressure to the upper compartment, causing the intermediate
plug to fall down and allow the two medicaments to mix and the thus resulting mixture
is sucked by the injection needle.
6. A two compartmented vial container as claimed in claim 5, wherein the aluminium
cap (4) is provided with a plastic cover (5) which can readily be filliped off.
7. An injection system comprising a syringe (8, 9, 10) and a vial container (1) as
claimed in any one of claims 3 to 6, in combination.