EP0295104A1

EP0295104A1 - Improvements in the use of vials

Info

Publication number: EP0295104A1
Application number: EP19880305283
Authority: EP
Inventors: Masamichi Sudo; Tamotsu C/O Daikyo Gomu Seiko Ltd. Okuda
Original assignee: DAIKYO GOMU SEIKO Ltd
Current assignee: DAIKYO GOMU SEIKO Ltd
Priority date: 1987-06-12
Filing date: 1988-06-09
Publication date: 1988-12-14
Also published as: JPS63197542U

Abstract

An improved method for storing at least two substances (6, 7) in complete independence from each other until use when they are required to be mixed utilising a compartmented vial (1) which comprises two compartments (A, B) connected by a constricted neck, in which is positioned a plug (2), and an ordinary rubber stopper (3) positioned in the mouth opening (C) of the vial. In use, a syringe needle (8) is pushed through the rubber stopper and air is injected into the upper compartment, thus causing a rise in pressure in the upper compartment forcing the plug to be displaced out of the neck and allowing the two compartments to communicate and their contents to combine to form a mixture, with which to charge the syringe body (9).

Description

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.
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.
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.
The following methods (I) and (II) are generally used to remove the partition wall:

Method (I)

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)

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.
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.
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.
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.
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.
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.
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.
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.

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.
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.
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.
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.
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.
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

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.

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

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.
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

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

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

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.
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".
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.
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.

Claims

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.