JP2003299734A - Syringe type kit pharmaceutical preparation and manufacturing method thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a syringe type kit pharmaceutical preparation using a serially and sequentially dispensing type syringe, which allows a stable production and sterilization by autoclave after packing and can prevent the generation of air bubbles within the first medicine solution, and also to provide a manufacturing method thereof. <P>SOLUTION: The syringe type kit pharmaceutical preparation comprises an injection cylinder and one or more intermediate sliding valves provided within the injection cylinder. A needle fitting part of the syringe type kit pharmaceutical preparation is sealed hermetically, and the space between the needle side of the injection cylinder and the intermediate sliding valve located nearest to the needle side of the injection cylinder is packed with a medicine solution. When manufacturing the syringe type kit pharmaceutical preparation, the needle fitting part of the injection cylinder is sealed hermetically and the injection cylinder is filled with the medicine solution. The intermediate sliding valve is then inserted into the injection cylinder from an opening on the plunger operation side and is moved to or near the surface of the medicine solution because of the depressurized atmosphere within the injection cylinder. The manufacturing method is characterized in that the depressurized atmosphere is rich in water soluble gas. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a syringe-type kit preparation, and more particularly, it has one or more intermediate slide valves inside a syringe barrel.
The present invention relates to a syringe-type kit preparation in which an injection needle mounting portion is tightly plugged, and at least a space inside a syringe barrel needle of an intermediate slide valve located closest to the syringe barrel needle side is filled with a drug solution.

[0002]

2. Description of the Related Art Since a syringe type kit preparation is filled with a necessary drug solution in advance in a syringe barrel, not only can it be rapidly operated, but a drug solution can be dispensed from an ampoule or a vial like a conventional injection. Since there is no need to suck it up inside, there is no risk of contamination such as glass powder or rubber pieces,
In addition, it is an excellent technology that has many advantages such as preventing medical accidents such as infection in advance.

Here, for example, treatment requires two or more kinds of drugs having different physical, chemical or pharmacological properties, but these drugs should be made into a mixed solution for the purpose of ensuring stability. That cannot be treated (for example, a combination of an acidic drug and an alkaline drug) or a therapeutic drug (second drug solution) causes severe pain at the site of administration, and therefore a second drug solution is used for the purpose of pain relief. It is known to administer a local anesthetic agent as a first drug solution in advance before administration of.

Of these, as the latter example, the first medicinal solution for osteoarthritis of the knee, periarthritis of the shoulder, etc. is a local anesthetic such as lidocaine hydrochloride, the influence of the thickness of the injection needle, and pH.
And osmotic pressure ratio is greatly different from body fluid, and with a therapeutic agent such as sodium hyaluronate that may cause severe pain to the affected area of the patient due to poor doctor's technique, or is widely used all over the world, A typical example is a combination with an induction anesthetic (propofol), which is known to give severe pain to venous blood vessels.

As such a syringe type kit preparation, a serial sequential dispensing type syringe which can be sequentially injected by the present inventors without mixing two or more kinds of drugs in one injection operation was used. The syringe-type kit preparation will be described.

FIG. 1 (a) is a model diagram showing an example of a syringe type kit preparation using a serial sequential dispensing type syringe capable of injecting two kinds of drugs in one operation.

The syringe of the kit formulation shown here has a needle connecting portion 1a at one end and an intermediate slide valve 3 and an intermediate slide valve 3 in a syringe barrel 1 having an opening at the other end on the plunger operation side. One plunger slide valve 2 is housed therein, and the inside of the injection cylinder 1 is watertightly divided by the slide valves 2 and 3 before and after. Further, the injection needle mounting portion 1a of the injection cylinder 1 is tightly plugged with a cap 4 made of an elastomeric material, and the first chemical solution 5 and the intermediate slide valve 3 in the injection cylinder needle side space of the intermediate slide valve 3. The space between the plunger slide valve 2 and the plunger slide valve 2 is filled with the second chemical liquid 6. In this example, the plunger slide valve 2 is provided with a removable plunger operating portion 2a.

A communication passage 1c is provided near the end of the side surface of the injection cylinder 1 of the injector near the needle side of the injection cylinder, and a part of the side wall projects radially with respect to the axis of the injection cylinder.

The intermediate slide valve 3 has a substantially cylindrical shape, and one side of the side surface of the plunger operating side (the rear side in the advancing direction) is provided with one annular lip 3a which makes one round in the circumferential direction. It abuts on the inner wall of the cylinder 1 and divides the space in front of and behind the injection cylinder in a watertight manner. On the other hand, the side of the intermediate slide valve 3 is in contact with the inner wall of the syringe barrel 1 on the side of the syringe barrel (the side of the advancing direction),
A holding portion 3b is provided so that the axis of the intermediate slide valve 3 having a substantially cylindrical shape can be aligned with the axis of the injection cylinder 1 even when the intermediate slide valve 3 slides. Unlike the annular lip 3a, this holding portion 3b does not go around the side surface of the intermediate slide valve 1 once,
The space between the annular lip 3a and the holding portion 3b on the side surface of
Since the intermediate sliding valve 1 communicates with and is integrated with the injection needle side space, the first chemical solution 5 is filled in the same manner as the injection needle side space and the space between the intermediate sliding valve and the plunger sliding valve. Has been done. Here, when an intermediate slide valve having two or more annular lips is used instead of the intermediate slide valve having such a shape, the closed space formed by the intermediate slide valve and the inner wall of the injection cylinder 1 is used. Air can be trapped and injected into the patient by an injection procedure, but such an inconvenience can be avoided by an intermediate slide valve having only one such annular lip. Further, a convex portion 3c is provided on the bottom surface of the intermediate slide valve 3 in the traveling direction. FIG. 1B is the LL of FIG.
3 is a cross-sectional view (model view) of FIG.

Prior to use of such a kit preparation, an injection needle 7 is attached to the injection needle connecting portion 1a of the injection cylinder 1 as shown in FIG. 1 (c).

At this time, if air bubbles are generated in the portion of the first drug solution 5 due to the operation of mounting the injection needle, etc., the air bubbles can be removed by operating the plunger operating portion 2a with the injection needle side facing up. . When the injection amount of the first drug solution 5 is particularly reduced, the plunger operating portion 2a is set at this stage.
To reduce the amount of the first chemical solution 5.

Next, the injection needle 7 is pierced into the injection-requiring site, and then the plunger operating portion 2a is moved to the needle mounting side of the injection cylinder 1 to inject the first drug solution 5 (see FIG. 2 (a)).

After that, when the operation of the plunger operating portion 2a is further continued, the second drug solution 6 is injected into the injection-requiring site this time. At this time, the intermediate slide valve 3 moves toward the needle side of the injection cylinder and reaches the tip of the injection cylinder. However, since the above-mentioned convex portion 3c provided on the intermediate slide valve 3 abuts on the bottom portion 1b of the injection cylinder, the intermediate slide valve 3 slides. Since the valve 3 does not come into close contact with the syringe barrel bottom portion 1b and the communication passage 1c serves as a bypass, even if these sliding valves move to the syringe barrel bottom portion 1b side, the injection needle 7 for the second medicinal solution 6 is provided.
The supply passage to the is secured.

FIG. 2B shows a state in which the operation of the plunger operating portion 2a is completed and the injection of the second drug solution 6 is completed (injection completed state). Normally, in this state, the injection needle is pulled out from the injection site, but when the injection amount of the second drug solution 6 is reduced, the injection needle is removed with the second drug solution 6 remaining in the syringe barrel 1. You can pull it out.

In such a serial sequential dispensing syringe type kit preparation, in the case where the first drug solution is a local anesthetic and the second drug solution is a therapeutic drug, the first drug solution 5 is injected into the site where it is injected. Since the second drug solution 6 is reliably injected, the second drug solution 6 can be injected without pain or with less pain even if the pH, osmotic pressure, temperature, etc. of the second drug solution differ greatly from the body fluid. Becomes

The example of the kit preparation using the serial sequential dispensing type syringe in which the communication passage is provided in the syringe has been described above. Next, the serial sequential using the ordinary syringe having no such communication passage. The dispensing syringe type kit preparation (slide valve type) will be described with reference to FIGS. 3 and 4.

First, FIG. 3 shows an example of a two-lip type slide valve type intermediate slide valve. The two-lip type intermediate slide valve is different from the one-lip type intermediate slide valve, and when combined with an ordinary syringe that does not have a communication passage, the chemical liquid does not enter between these lips, so the chemical liquid is not wasted. Therefore, the filled liquid medicine can be used more effectively. The number of lips may be three or more.

FIG. 3 (a) shows a sliding valve body H1 of a two-lip type intermediate sliding valve. In this example, two annular lips h1 are provided. FIG. 3B shows a slider I1 that forms the intermediate slide valve Hd together with the slide valve body H1. The slider I1 includes a contact portion i1 and a slide portion i2, and the intermediate slide valve body portion through hole h of the slide portion i2.
3 Side opening i4 together with widening part i6 on the surface in contact with the inner wall surface
And a front opening i3 that is opened in the space on the side of the injection cylinder needle of the intermediate slide valve, and these front opening i3 and side opening i
4 is provided inside the slide part i2, and the slider I1 is further connected to the intermediate slide valve body part H1.
On the other hand, the side opening i4 is closed by the wall surface of the intermediate sliding valve body portion through hole h3 when the slider I1 is closed before sliding to the plunger operating side (state of FIG. 3C).
Is opened by sliding to the plunger operating side with respect to the intermediate sliding valve body H1 (state shown in FIG. 3D), the side opening i4 is against the drug (second drug) on the plunger operating side. The second medicine on the plunger operating side can be supplied to the injection cylinder needle side of the intermediate slide valve through the liquid passage hole i5. The slider I1 is provided with a check portion i7 so that the slider I1 does not move from the sealing position to the injection cylinder needle side with respect to the intermediate slide valve body H1.

Operation method of an example of a kit preparation using a serial sequential dispensing syringe (three-liquid sequential injection type) having such a slide valve type intermediate slide valve Hd as shown in FIGS.
A specific description will be given using (f). Note that the reference numerals are used in common for corresponding members in FIGS. 1 and 2.

FIG. 4A shows the intermediate slide valve Hd described above. In this example, the intermediate slide valve Hd is an intermediate slide valve located closest to the injection cylinder needle side (hereinafter referred to as “first intermediate slide valve”).

Further, the intermediate sliding valve H shown in FIG.
d '(hereinafter referred to as "second intermediate slide valve") is an intermediate slide valve located closer to the plunger operating side than the first intermediate slide valve. These intermediate slide valve Hd and intermediate slide valve Hd ′ are shown in FIG.
As shown in (c), it is arranged in the injection cylinder 1 (normal, integrally formed injection cylinder).

Hereinafter, in the case of a syringe having a plurality of intermediate slide valves, the intermediate slide valve arranged closest to the injection cylinder needle side like the intermediate slide valve Hd is referred to as "first intermediate slide valve", and The intermediate slide valves, such as the intermediate slide valve Hd ′, which are arranged closer to the plunger operating side than the first intermediate slide valve are collectively referred to as “second intermediate slide valve”.

In addition, an example in which three liquids can be sequentially injected without mixing will be described below, but a syringe that can sequentially inject without mixing four liquids or more increases the number of second intermediate slide valves. Therefore, a syringe that can be sequentially injected without mixing the two liquids can be similarly achieved by not using the second intermediate slide valve together.

The second intermediate slide valve Hd 'is in contact with the inner wall of the injection cylinder and has an annular lip h1 and an annular lip h1 for watertightly dividing the injection cylinder needle side space and the plunger operation side space of the intermediate slide valve.
1 is a through hole h3 ′ for bypassing the space between the injection needle side and the plunger operating side, a sealing means for sealing the through hole, and the intermediate slide valve Hd ′ is the injection needle end point or the end point due to the injection operation. An intermediate slide valve for a syringe having a seal release means for releasing the above-mentioned seal when it reaches the vicinity, which is in contact with the inner wall of the syringe barrel 1 and the syringe barrel needle side space of the second intermediate slide valve hd 'and the plunger operation. An annular lip h1 that divides the side space in a watertight manner, and a through hole h that bypasses the annular lip h1 and connects the syringe barrel side space and the plunger operating side space.
3 ', sealing means for sealing the through hole h3', and sealing releasing means for releasing the sealing when the intermediate slide valve Hd 'reaches the end point on the needle side of the injection cylinder 1 or near the end point by an injection operation. And the second intermediate slide valve has the annular lip h1.
And a through hole h3 'and an intermediate sliding valve body H1', an abutting portion i1 'and a sliding portion i2', and the sealing means and the sealing releasing means are advanced to the injection cylinder needle side of the intermediate sliding valve. Accordingly, the contact portion i1 'which comes into contact with another intermediate slide valve located in front of the injection needle side of the intermediate slide valve and the corresponding contact portion i1 are located on the plunger operation side with respect to the'intermediate slide valve main body H1'. A slide part i2 that drives the sealing means by the relative movement to release the sealing of the through hole h3 'by the sealing means.
And a second intermediate slide valve for a syringe.

Further, in the second intermediate slide valve Hd ', the contact portion i1' and the slide portion i2 'are integrated to form a slider I1', and the slider I1 'is the intermediate slide valve body. The slide valve i2 'is housed in the through hole h3' of the portion H1 'and slidable toward the plunger operating side with respect to the intermediate slide valve body H1'.
1'A through-hole h3 'is provided with a side opening i4' on the surface in contact with the inner wall surface, and a front opening i3 'is opened in the space of the intermediate slide valve Hd' on the side of the injection needle, and these front opening i3 'and side opening i4. The liquid passage hole i5 that communicates with the'and the slide portion i2 '
Further, when the slider I1 'is closed before the slider I1' slides toward the plunger operating side with respect to the intermediate slide valve body H1 ', the side opening i4' has the intermediate slide valve body H.
1'Through hole h3 'Sealed by the wall surface, slider I1'
Is opened by sliding to the plunger operating side with respect to the intermediate slide valve body H1 ', the side opening i4' is exposed to the drug on the plunger operating side, and the drug on the plunger operating side opens the liquid passage hole i5 '. It is the second intermediate slide valve for a syringe that can be supplied to the syringe barrel side of the intermediate slide valve Hd '.

In this example, the length of the slider I1 'is substantially equal to the thickness of the intermediate slide valve body H1', and the intermediate slide disposed in front of the through hole h3 'of the intermediate slide valve body H1'. A recess h5 having a size corresponding to the check portion protruding from the valve operating side to the plunger operating side is provided.

The syringe shown in FIG. 4 (c) having one such first intermediate slide valve Hd and one second intermediate slide valve Hd 'can be handled in the same manner as an ordinary syringe. . In FIG. 4, reference numeral 1 denotes a glass injection cylinder (integral type, normal shape) that is easily sterilized and is mass-produced at low cost.

FIG. 4 (c) shows a state in which the sealing by the cap 4 (not shown) made of an elastomeric material attached to the injection needle connecting portion 1a is released and the injection needle 7 is attached. FIG. 4D shows a state where the injection of the first liquid has been completed (the slider I1 has already been opened when the slider I1 has slid to the plunger operating side), and FIG. 4E shows a state where the injection of the second liquid has been completed (slider). I1 'is the slider I1
After sliding on the plunger operating side, it is in the open state.

The slide amount of the slide I1 'of the second intermediate slide valve Hd' to the plunger side corresponds to the slide amount of the slide I1 of the first intermediate slide valve Hd to the plunger side), and FIG. (F) shows the state where all the injection operations have been completed. At this time, the plunger slide valve 2 has a second
Since there is no gap between the plunger slide valve 2 and the second intermediate slide valve Hd 'due to the concave portion 2b corresponding to the slide amount of the slide I1' of the intermediate slide valve Hd 'on the plunger side, the injection pipe for the drug solution is provided. Almost no residue is left inside.

As described above, FIG. 2A and FIG.
Although the two types of syringes shown in (a) are easy to operate, they can be sequentially injected without being mixed with each other without being affected by the operating environment (temperature) and the viscosity of the filled chemicals. In addition, it is an in-line sequential dispensing syringe for kit preparation, which has an excellent amount of drug solution remaining in the syringe barrel.

The filling of the drug solution in such a serial sequential dispensing type injector has been carried out by applying the method of filling the drug solution in the kit preparation for single-liquid injection.

Here, the method for filling the kit preparation for single liquid injection will be described with reference to FIG. FIG. 5 (a) shows an injection cylinder 1 having a normal shape. The injection needle connecting portion 1a is directed downward,
And it is sealed by the cap 4.

A predetermined amount of a predetermined drug solution 5'is introduced into the injection cylinder 1 (see FIG. 5 (b)). The pressure inside the injection cylinder and in the vicinity of the plunger operation side opening is reduced before the introduction of the drug solution or after the drug solution is introduced.

Under a reduced pressure atmosphere, the plunger slide valve 3 is shallowly inserted into the opening on the plunger operation side of the injection cylinder (Fig. 5 (c)).
Then, the depressurization in the vicinity of the opening of the syringe plunger on the operating side is released to move the plunger slide valve 3 to the liquid surface of the drug solution 5'or near the liquid surface (Fig. 5).
(See (d)) The filling operation is completed.

There is no problem in the method of filling the drug solution in such a single-liquid injector type kit, and the obtained product is 95
Since it was possible to sterilize and sterilize by autoclave at ~ 121 ° C, application of this method was being conducted to investigate the filling of the chemical solution into the serial sequential dispensing syringe.

An example using a two-liquid sequential dispenser type syringe will be described with reference to FIG. First, the needle mounting part 1
The first drug solution 5 is injected into the injection cylinder 1 in which a is sealed with a (see FIG. 6 (a)), and the intermediate slide valve 3 is moved to the plunger of the injection cylinder while the inside of the injection cylinder 1 is in a reduced pressure atmosphere. It is inserted shallowly into the opening on the operation side (see FIG. 6B), and then the intermediate slide valve 3 is moved to the liquid surface of the chemical liquid 5 or the vicinity thereof by the pressure of the atmosphere outside the injection cylinder (FIG. 6C). )reference).

Then, a predetermined amount of the second chemical 6 is filled (see FIG. 6 (d)), and the plunger slide valve 2 is operated to operate the plunger of the injection cylinder while the inside of the injection cylinder is in a reduced pressure atmosphere. It is inserted into the side opening shallowly (see FIG. 6 (e)), and then the plunger slide valve 2 is moved to the liquid surface of the chemical liquid 4 or near the liquid surface by the pressure of the atmosphere outside the injection cylinder (FIG. 6).
(Refer to (f)) Filling is completed.

In the above method, the pressure reducing condition is set to the lower limit value (usually 667 to 2667 Pa) so that the sliding valve moves sufficiently when the pressure is released, and the loss of the amount of the liquid chemical due to the scattering of the liquid due to the sudden boiling of the liquid chemical. In order to prevent the occurrence of defective products due to the above, it was performed while cooling the drug solution and the syringe, or using a previously cooled drug solution and the syringe, or cooling from the outside of the syringe. However, it has been found that this method causes various problems.

If the pressure around the opening of the injection cylinder is reduced before the second drug solution is filled, the intermediate slide valve 3 moves upward as shown in FIG. 7, and there is no space for filling the second drug solution. There was a problem that the filling failed at this time.

Even if the filling is successfully completed, sterilization and sterilization by an autoclave (95-1
When the treatment at a temperature of about 21 ° C.) is performed, bubbles are generated in the space filled with the first chemical liquid, the intermediate sliding valve 3 moves to the plunger operating side, and as a result, the plunger sliding valve comes off, Problems such as the loss of the second chemical liquid occur (see FIG. 8).

Further, in the case of the kit preparation using the slide valve type serial sequential dispensing type injector as shown in FIG. 4, the slider I1 moves to the plunger operating side even if the sterilization treatment is performed at a lower temperature, A drawback such as mixing of the drug solution that should have been partitioned by the intermediate slide valve Hd occurred (an example of a two-solution serial sequential dispensing syringe kit preparation is shown as a model in FIG. 9).

Further, even if the sterilization after filling is unnecessary and the heat treatment is not performed, air bubbles may be mixed in the first liquid of the manufactured product, and the air bubbles are many fine air bubbles. However, it is often difficult to remove even by the air bubble removal operation before the injection operation, and if subcutaneous injection is performed with the air bubbles remaining, the muscle or skin may be dissected, which may cause unnecessary pain to the patient. is there. Further, these bubbles are air, and if the components of the first chemical liquid are unstable with respect to oxygen in the air, it is considered that there will be a serious problem in terms of storability.

[0043]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned conventional problems, namely, it has one or more intermediate slide valves inside the syringe barrel, and the injection needle mounting portion is tightly plugged, and A method for producing a syringe-type kit preparation in which a liquid medicine is filled in a space on the side of the syringe barrel needle of the intermediate slide valve located closest to the syringe barrel needle side of the intermediate slide valve, the method comprising: After injecting the drug solution into the cylinder, after inserting the intermediate slide valve into the plunger operation side opening of the injection cylinder whose inside is in a reduced pressure atmosphere, move the intermediate slide valve to the drug solution surface or near the liquid surface. Provided is a method for producing a syringe-type kit preparation, which is capable of stable production and sterilization by autoclave after filling, and which is a product in which bubbles are not generated in the first drug solution. Is intended to .

[0044]

In order to solve the above-mentioned problems, the method for producing a syringe-type kit preparation of the present invention has, as described in claim 1, one or more intermediate slide valves inside the syringe barrel. A method for producing a syringe-type kit preparation in which the injection needle mounting portion is tightly plugged, and a liquid medicine is filled in a space on the syringe barrel needle side of the intermediate slide valve located closest to the syringe barrel needle side of the intermediate slide valves, After injecting the medicinal solution into an injection cylinder having a sealing plug on the injection needle mounting part, inserting an intermediate slide valve into the plunger operation side opening of the injection cylinder whose inside has a reduced pressure atmosphere, and then inserting the intermediate slide valve into In the method for producing a syringe-type kit preparation in which the liquid medicine is moved to or near the liquid surface, the reduced-pressure atmosphere is a reduced-pressure atmosphere rich in water-soluble gas.

With such a construction, stable production is possible, and sterilization by an autoclave after filling is also possible,
Further, a product in which no bubbles are generated in the first chemical liquid can be obtained.

Furthermore, as described in claim 2, the injection of the medicinal solution into the injection cylinder in which the injection needle mounting portion is tightly plugged,
The effect of the present invention can be obtained more reliably by carrying out in a reduced pressure atmosphere rich in water-soluble gas.

Further, the effect of the present invention can be reliably obtained by using a degassed chemical solution as the chemical solution as described in claim 3.

Further, the depressurized atmosphere inside the syringe barrel is formed by being sucked from the opening portion on the plunger operating side of the syringe barrel, and the water-soluble gas is supplied to the vicinity of the liquid level of the drug solution inside the syringe barrel. As a result, the required amount of water-soluble gas can be reduced and the atmosphere can be easily replaced, which enables rapid production.

Furthermore, as described in claim 5, when the water-soluble gas is carbon dioxide or water vapor, the range of application of the present invention can be expanded, and
By using steam, it is possible to prevent the occurrence of accidents due to bumping of the chemical liquid during the manufacturing process, and it is possible to contribute to the improvement of yield. On the other hand, when carbon dioxide is used as a water-soluble gas, the manufacturing apparatus can be simplified.

[0050]

BEST MODE FOR CARRYING OUT THE INVENTION One or more intermediate slide valves are provided inside an injection cylinder, an injection needle mounting portion is tightly plugged, and an intermediate slide valve located closest to the injection needle side of the intermediate slide valves. As the syringe type kit preparation in which the space in the needle side of the valve operating valve is filled with a drug solution, the syringe using the syringe by the present inventors, which has been described in detail in the above description of the prior art, is disclosed in JP-A-10-5748.
No. 6, JP-A-10-80485, and JP-A-8-
Such as those proposed in Japanese Patent No. 294532, etc. 1
With more than one intermediate slide valve, the needle mounting part is tightly plugged,
Moreover, it is sufficient that the syringe is one in which the space inside the syringe barrel needle side of the intermediate slide valve located closest to the syringe barrel needle side of the above-mentioned intermediate slide valves is filled with the drug solution.

However, in the manufacturing method according to the present invention, the space between the syringe barrel needle side of the intermediate slide valve that is located closest to the syringe barrel needle side of the intermediate slide valve is filled with a powdered drug, or is simply gas. Alternatively, it cannot be applied to a syringe-type kit preparation filled with air.

In the present invention, it is necessary that the injection needle mounting portion of the injection cylinder is tightly plugged, but a so-called accessory such as an injection needle or a tube is mounted on the injection needle mounting portion of the injection cylinder, and If the injection needle or the accessory is sealed by a sealing means such as a cap or a cock, as a result, the injection needle mounting portion itself is hermetically sealed, and this case is also included in the present invention.

The reduced pressure atmosphere in the present invention needs to be such that the filled liquid medicine does not boil and does not scatter from the syringe. It depends on the properties (solvent, temperature, etc.) of the liquid medicine to be filled, but it is usually 670 Pa or more and 10000 Pa or less, preferably 2500 Pa or more 7
It is 000 Pa or less.

Further, in the present invention, the depressurized atmosphere is a depressurized atmosphere rich in water-soluble gas in the liquid medicine filled in the space on the syringe barrel needle side of the intermediate slide valve located closest to the syringe barrel needle side. is necessary. The fact that the reduced pressure atmosphere is rich in water-soluble gas means that 50% or more of the total pressure of the gas in the reduced pressure atmosphere is the partial pressure of the water-soluble gas. In addition, 70% of the total pressure of the gas in the reduced pressure atmosphere
% Or more is preferably the partial pressure of the water-soluble gas,
More preferably, it is 80% or more.

Such a reduced-pressure atmosphere rich in water-soluble gas can be obtained by temporarily replacing the atmosphere, such as air, with a water-soluble gas and then reducing the pressure. It can be easily obtained by introducing a small amount of water-soluble gas into the atmosphere and depressurizing it again, and repeating "water-soluble gas and re-depressurizing" once or several times. . The latter is desirable because it requires less amount of water-soluble gas.

However, the reduced pressure atmosphere inside the syringe barrel is formed by sucking it from the plunger operating side opening of the syringe barrel, and the water-soluble gas is supplied near the liquid level inside the syringe barrel, so that If a reduced pressure atmosphere rich in water-soluble gas is formed inside, the amount of water-soluble gas used can be made extremely small and batch replacement work is unnecessary It is more preferable because the atmosphere can be replaced.

As described above, by sucking from the opening on the plunger operation side of the syringe barrel, the inside of the syringe barrel is kept in a reduced pressure atmosphere, and the gas soluble in water is supplied near the liquid surface of the liquid medicine inside the syringe barrel. Regarding the reduced pressure atmosphere to be a reduced pressure atmosphere rich in water-soluble gas, FIG.
This will be described with reference to FIG.

10 (a) to 10 (d), the atmosphere inside the syringe barrel 1 is sucked from the opening on the plunger operating side of the syringe barrel 1 as indicated by the thick arrow.

On the other hand, as for the water-soluble gas, as shown in FIG. 10 (a), the introduction pipe 10 for introducing the water-soluble gas has the tip of the introduction pipe 10 which is the liquid of the medicinal solution 5 in the syringe barrel 1. It is desirable to insert it so that it is located near the surface and supply it from its tip.

However, for example, as shown in FIG. 10B, the tip of the introducing pipe 10 may be bent toward the plunger operating side, and at this time, the gas flow of water-soluble gas is the liquid of the chemical liquid 5. Since the surface is not disturbed, the dissolved amount of the water-soluble gas in the chemical liquid 5 can be made smaller than that in the case of FIG.

As shown in FIG. 10C, even if the tip of the introduction pipe 10 is outside the injection cylinder, the water-soluble gas supplied from the tip is supplied near the liquid surface of the drug solution 5. However, these cases are also included in the present invention.

In the above, not only after injecting the drug solution, but also during injecting the drug solution into the syringe barrel in which the injection needle mounting portion is sealed, and further before the injection, suction from the opening on the plunger operation side of the syringe barrel. It is desirable that a gas soluble in water is supplied to the inside of the syringe barrel. That is, FIG. 10 (d)
As shown in Fig. 10, the liquid medicine may be introduced into the injection cylinder 1 while supplying the water-soluble gas from the introduction pipe 10 into the injection pipe 1 (Fig. 10 (d) shows injection of the liquid medicine introduction pipe 11). Tube 1
An example in which the drug solution 4 is introduced by inserting it into the inside is shown).

When the water-soluble gas is supplied into these syringes, the amount of the water-soluble gas supplied is such that the atmosphere of the syringe is replaced with the water-soluble gas. It is sufficient if the pressure is sufficient, and the pressure in the syringe barrel needs to be kept sufficiently decompressed with respect to the atmospheric pressure.

In the present invention, the water-soluble gas is preferably carbon dioxide or water vapor, and may be a gas in which carbon dioxide and water vapor are mixed. A gas such as oxygen, nitrogen or air has a low solubility in water, so that a sufficient effect cannot be obtained. In addition, in the case of other inorganic / organic gases such as other ammonia and hydrogen chloride, they may be dissolved in the drug solution and introduced into the body, so the safety to the living body or the effect on the drug solution It is necessary to select after examining in advance.

According to an experiment conducted in advance in the present invention,
Even when carbon dioxide was used, the amount of dissolution in the drug solution was extremely small under reduced pressure, so no effect on pH was observed. Since carbon dioxide is a gas at room temperature, it can be handled easily and the device can have a simple structure, but it can be released as bubbles from the heated chemical solution during heat sterilization / sterilization after filling. Considering the properties, the influence on the chemicals, etc., it is more preferable to use steam as the water-soluble gas.

When water vapor is used as a water-soluble gas, the inside of the syringe is in a depressurized state.
Under the introduction pipe 10 of (a) to (d), the temperature is higher than the temperature of the drug solution 5 in the syringe barrel 1 (usually 5 ° C or higher, preferably 10 ° C).
By connecting to a water tank (sterile water is used and degassed beforehand) kept at the above high temperature, it vaporizes from the nozzle holes of appropriate size provided at the tip of these introduction pipes to become steam. Therefore, its supply is extremely easy. Furthermore, at this time, bumping of the chemical liquid 5 can be effectively prevented, so that failure of filling such as scattering of the chemical liquid due to bumping can be prevented in advance, and the degree of vacuum can be adjusted due to the influence of the temperature of the chemical liquid 5. Is unnecessary.

In the present invention, it is desirable that the first chemical liquid to be injected into the injection cylinder having the injection needle mounting portion provided with a hermetically-sealed portion be one in which dissolved air has been sufficiently removed by a degasser or the like in advance.

As the degasser, a method in which a hollow fiber membrane and a depressurizing means are combined (a hollow fiber is placed in a depressurized atmosphere and continuously degassed when a chemical solution passes through the hollow fiber), batch type The method of putting in a closed container and depressurizing the inside can be mentioned. At the time of this degassing treatment, the temperature of the chemical solution may be room temperature, but the effect is high when it is heated to 40 ° C. If the stability of the chemical solution is not impaired, higher temperature may be used. The chemical solution after the degassing is handled, for example, in a closed system so as not to come in contact with air as much as possible.

Furthermore, it is desirable to similarly remove the dissolved air in advance for the second and subsequent chemical liquids and all the chemical liquids used for filling.

When injecting a drug solution into an injection cylinder having a sealing plug on the injection needle mounting portion, the atmosphere and the drug solution are mixed with each other even under a reduced pressure atmosphere rich in water-soluble gas. Make sure that the inner wall does not come into contact with the drug solution as much as possible, and that bubbles do not form and that it is done as quickly as possible.

Chemical liquid at this time (the same applies to the second and subsequent chemical liquids)
The temperature is preferably room temperature, or is higher than 35 ° C. and lower than 40 ° C., or is heated to a higher temperature within the range where the stability of the chemical solution is not impaired. At this time, using a cold chemical solution, or if the chemical solution is supplied while being cooled, it dissolves a gas such as oxygen or nitrogen that is originally difficult to dissolve in water, and when it reaches room temperature after filling, or During heat sterilization, these may form bubbles and the effect of the present invention may not be obtained. When heating the chemical solution, it is necessary to adjust the depressurized state so that bumping of the chemical solution does not occur.

Immediately after the injection of the drug solution, the intermediate slide valve is inserted into the plunger operation side opening of the injection cylinder (Fig. 11 (a)).
Then, the intermediate slide valve is moved to the liquid surface of the chemical liquid or the vicinity of the liquid surface by the pressure of the atmosphere outside the injection cylinder (first stopper) (see FIG. 11 (b)). Specifically, the atmosphere outside the syringe cylinder near the opening on the plunger operation side is also decompressed, an intermediate slide valve is inserted into the opening on the plunger operation side, and then the atmosphere outside the syringe cylinder near the opening on the plunger operation side is at atmospheric pressure. By returning to the intermediate slide valve 3
Moves to the liquid surface or near the liquid surface (FIG. 11).
(See (b)).

The position of insertion of the intermediate slide valve into the plunger operation side opening of the syringe barrel is usually shallow, and it is sufficient that at least one of the annular lips abuts the inner wall of the syringe barrel. Although a special jig or the like for deeply inserting the valve is not required, it may change to some extent depending on the material of the sliding valve or the like, whether or not a lubricant is used in combination, so the optimum position should be considered in advance.

Further, the intermediate slide valve may not be moved by the pressure difference between the inside and outside of the injection cylinder as described above, but may be mechanically moved by a cylinder driven by an actuator, or both may be used together. .

After the first stopper, the second chemical solution is injected, preferably in a reduced pressure atmosphere rich in water-soluble gas (see FIG. 11 (c)). Then, in a reduced pressure atmosphere rich in water-soluble gas, the intermediate slide valve or the plunger slide valve was inserted into the plunger operation side opening of the injection cylinder (Fig. 11).
(See (d)), and then immediately similarly, depressurize the atmosphere around the syringe barrel. When this depressurization is released, the intermediate slide valve or the plunger slide valve moves to the liquid surface of the second chemical liquid or in the vicinity thereof (second stopper) (see FIG. 11 (e): This example shows the plunger slide). Valve 2 is used).

It is necessary that the reduced pressure atmosphere during the second stoppering is the same as or higher than the reduced pressure atmosphere during the first stoppering. Even when the third and subsequent plugging operations are performed thereafter, it is necessary that the pressure is the same as or higher than the pressure of the atmosphere at the time of the previous stoppering operation, and it is desirable to gradually increase the pressure gradually.

In this way, by the steps up to the second tapping,
Alternatively, the desired serial sequential dispensing kit preparation can be stably obtained by repeating the same "chemical solution injection and stoppering" as many times as necessary, and the obtained serial sequential dispensing kit preparation can be obtained. Does not cause any problem during sterilization treatment by an autoclave after filling, and is a product in which bubbles are not generated in all chemical liquids.

[0078]

EXAMPLES The method for producing the syringe-type kit preparation of the present invention will be specifically described below. <Syringe kit formulation A of lidocaine and neuralgia therapeutic agent
> 0.5m Lidocaine aqueous solution 2m as the first chemical
L, the second drug solution is a neuralgia therapeutic drug solution 2 mL (medicine solution 1 m
Syringe type kit preparation A was prepared using a two-component serial sequential dispensing syringe having 1 mg of dibucaine hydrochloride, 3 mg of sodium salicylate and 2 mg of calcium bromide mixed per L. This kit formulation is
It is an excellent kit preparation capable of preventing the severe pain caused when the therapeutic agent for neuralgia is injected into a joint or the like.

The filling of the first liquid was performed as shown in FIG. That is, the inside of the injection cylinder 1 (a glass injection cylinder for 5 mL) having a sealing plug 4 attached to the injection needle mounting portion is kept in a depressurized state (about 5000 Pa) by continuously suctioning from the opening on the plunger operation side, and then the inside of the injection cylinder. While introducing a very small amount of carbon dioxide as a water-soluble gas from the gas cylinder from the introduction pipe 10 inserted in 1, the syringe was also inserted in the syringe 1 while keeping the inside of the syringe in a reduced pressure atmosphere rich in carbon dioxide. 0.5 was previously degassed with a degasser from the chemical liquid introducing pipe 11 and then kept degassed.
% Lidocaine aqueous solution (35 ° C.) was supplied in an amount of 2 mL.

At this time, the gas atmosphere inside the syringe barrel was sampled with a gas tight syringe and analyzed by gas chromatography. As a result, the sum of the concentrations of carbon dioxide gas and water vapor, both of which are water-soluble gases, was 90 It was confirmed that the percentage was over.

Then, after inserting the intermediate slide valve into the plunger operating side opening of the syringe barrel, the atmosphere outside the syringe barrel was returned to normal pressure. At that time, the intermediate slide valve moved to the surface of the chemical liquid due to the pressure difference.

Next, the second drug solution, a neuralgia therapeutic drug solution, was filled. At this time, as in the case of filling the first liquid, the inside of the syringe barrel is kept in a depressurized state (about 6000 Pa), and a very small amount of carbon dioxide is supplied as a gas soluble in water to reduce the pressure inside the syringe barrel rich in carbon dioxide. While maintaining the atmosphere, 2.5 mL of the neuralgia therapeutic drug solution (35 ° C.), which had been degassed by a degasser in advance and then kept degassed, was supplied from the drug solution introduction pipe that was also inserted into the syringe. It was confirmed that the atmosphere inside the syringe barrel at this time also had a sum of the concentrations of carbon dioxide and water vapor, which are water-soluble gases, of 90% or more of the total.

Furthermore, after inserting the plunger slide valve into the plunger operating side opening of the injection cylinder, the atmosphere outside the injection cylinder was returned to normal pressure. At that time, due to the pressure difference, the plunger sliding valve moves to the liquid surface of the liquid medicine, and thus the syringe type kit preparation A according to the present invention.
was gotten.

This syringe type preparation A was set in an autoclave and sterilized at 121 ° C. for 20 minutes. After that, it was observed when the temperature returned to room temperature, but neither the intermediate sliding valve nor the plunger sliding valve moved, and there were no bubbles inside.

<Syringe Kit Formulation B of Lidocaine and Sodium Hyaluronate> A two-liquid type having 0.5% lidocaine aqueous solution (2 mL) as the first drug solution and 1% sodium hyaluronate aqueous solution (2.5 mL) as the second drug solution. A syringe type kit preparation using a serial sequential dispensing type syringe was prepared. This kit preparation is an excellent kit preparation that can prevent pain in advance when an aqueous sodium hyaluronate solution is injected into the joint cavity of the knee or shoulder.

The syringe used has the slide valve type intermediate slide valve Hd of FIG. 3 (b) as an intermediate slide valve.
As shown in (a), a two-component serial in-line dispensing syringe (5
mL), and a general inexpensive plastic syringe can be used.

In use, as shown in FIG. 12 (b), the cap 4 made of a material having an elastomeric property is removed and then the injection needle 7 is mounted and the plunger sliding valve 2 is attached.
Attach the plunger operation part to.

The inside of the glass injection cylinder 1 in which the injection needle connecting portion 1a is sealed with the cap 4 is sucked from the opening on the plunger operating side to reduce the pressure inside (see FIG. 12 (c)), and the suction is continued thereafter. And decompressed (about 5000P
While keeping the condition a), a very small amount of carbon dioxide as a water-soluble gas was supplied from the gas cylinder into the syringe 1 and was inserted into the syringe while maintaining the inside of the syringe in a reduced pressure atmosphere rich in carbon dioxide. 0.5 was previously degassed with a degasser from the chemical liquid introducing pipe 11 and then kept degassed.
% Lidocaine aqueous solution (35 ° C.) was charged (see FIG. 12D). It was confirmed that the atmosphere inside the syringe barrel at this time also had a sum of the concentrations of carbon dioxide and water vapor, which are water-soluble gases, of 90% or more of the total.

After that, the introduction pipe 10 and the drug solution introduction pipe 11 are promptly removed, and then the slide valve type intermediate slide valve Hd is inserted into the opening of the injection barrel 1 on the plunger operation side (see FIG. 12).
(See (e)), the intermediate slide valve was moved to the first liquid surface of the liquid medicine by returning the outside of the injection cylinder to normal pressure (see FIG. 12 (f)).

Next, 2.5 mL of a 1% aqueous sodium hyaluronate solution, which is the second chemical solution, was similarly treated, except that
The depressurization condition was slightly relaxed to about 6000 Pa, the filling was performed, and then the plunger sliding valve 2 was stoppered to obtain a syringe type kit preparation B shown in FIG. 12 (a).

This syringe type preparation B was set in an autoclave and sterilized at 100 ° C. After that, when the temperature was returned to room temperature, it was observed, but neither the slide valve type intermediate slide valve nor its slider I1 slide valve or the plunger slide valve moved, and no bubbles were generated inside.

[0092]

INDUSTRIAL APPLICABILITY The method for producing a syringe-type kit preparation of the present invention is excellent in that stable production and sterilization treatment by an autoclave after filling are possible, and a product in which bubbles are not generated in the first drug solution can be obtained. It is a syringe type kit preparation.

[Brief description of drawings]

FIG. 1 (a) is a model diagram showing an example of a syringe type kit preparation using a serial sequential dispensing type syringe capable of injecting two kinds of drugs with one operation. (B) It is sectional drawing (model figure) in LL of FIG.1 (a). (C) It is a figure which shows the state with which the injection needle was attached.

FIG. 2 (a) is a diagram showing a state in which the injection of the first drug solution 5 is completed. (B) It is a figure which shows the state (injection completion state) in which the operation of the plunger operation part 2a is completed and the injection of the second drug solution 6 is completed.

FIG. 3 is a diagram showing an example of a two-lip type slide valve type intermediate slide valve. (A) It is a figure which shows the sliding valve main-body part H1 of a 2 lip type intermediate sliding valve. (B) It is a figure which shows the slider I1 which forms the intermediate slide valve Hd with the slide valve main-body part H1. (C) When the slider I1 is sealed before sliding on the plunger operating side with respect to the intermediate sliding valve body H1 (see FIG. 3).
It is a figure which shows the state of (c) state. (D) It is a figure which shows the state at the time of opening which the slider I1 slid to the plunger operation side with respect to the intermediate slide valve main-body part H1.

FIG. 4 is an explanatory diagram for an operation method of an example of a kit preparation using a serial sequential dispensing syringe (three-liquid sequential injection type) having a slide valve type intermediate slide valve Hd. (A) It is a figure which shows the intermediate slide valve Hd. (B) It is a figure which shows intermediate sliding valve Hd '. (C) Diagram showing a kit preparation using a serial sequential dispensing type syringe (three-fluid sequential injection type) equipped with one first intermediate slide valve Hd and one second intermediate slide valve Hd ′ (injection needle It is in a mounted state). It is a figure which shows the state where (d) injection of the 1st liquid was completed. (E) It is a figure which shows the state which injection of the 2nd liquid was completed. (F) It is a figure which shows the state where all the injection operations were completed.

FIG. 5 illustrates a method for filling a kit preparation for single liquid injection with reference to FIG. (A) It is a figure which shows the injection cylinder 1 of a normal shape. (B) It is a figure which shows the state which inject | poured the predetermined chemical | medical solution 5'into the inside of the injection cylinder 1. (C) It is a figure which shows the state which inserted the plunger sliding valve 3 into the operation side opening part of the injection cylinder shallowly in decompression atmosphere. (D) It is a diagram showing a state where the plunger sliding valve 3 is moved to the liquid surface of the chemical liquid 5 ′ or near the liquid surface and the filling operation is completed.

FIG. 6 is a diagram illustrating an example in which the method shown in FIG. 5 is used with a two-liquid sequential dispensing syringe. (A) First in the injection cylinder 1 in which the needle mounting portion 1a is sealed.
It is a figure which shows the state which inject | poured the chemical | medical solution 5. (B) It is a figure which shows the state which inserted the intermediate slide valve 3 into the plunger operation side opening part of the injection cylinder shallowly in the state where the inside of the injection cylinder 1 was in a pressure-reduced atmosphere. (C) It is a figure which shows the state which moved the intermediate slide valve 3 to the said chemical | medical solution 5. (D) It is a figure which shows the state which filled the 2nd chemical | medical solution 6 with predetermined amount. (E) It is a figure which shows the state which inserted the plunger slide valve 2 into the plunger operation side opening part of the injection cylinder shallowly in the state where the inside of the injection cylinder became a decompression atmosphere. (F) It is a figure which shows the state which moved the plunger sliding valve 2 to the chemical | medical solution 4.

FIG. 7 shows a problem that the intermediate sliding valve 3 moves upward due to the method shown in FIG. 6, and there is no space to fill the second chemical liquid, and at this time, filling fails. It is a figure explaining.

FIG. 8 is a diagram showing the method shown in FIG. 6, in which the plunger sliding valve is disengaged as a result of sterilization / sterilization by an autoclave even after the filling is completed successfully.
It is a model figure which shows the problems, such as a 2nd chemical | medical solution being lost.

FIG. 9 is a model diagram showing a problem that occurs when a kit preparation using the slide valve type serial sequential dispensing syringe as shown in FIG. 4 is autoclaved.

FIG. 10 is a diagram illustrating a manufacturing method of the present invention. (A)-(c) It is a model figure explaining three methods which introduce | transduce the gas soluble in water into a syringe. (D) A model diagram showing a state in which a water-soluble gas is introduced into the syringe even during filling with the drug solution.

FIG. 11 is a diagram illustrating a process after the injection of the first chemical liquid is completed. (A) It is a figure which shows the state which inserted the intermediate slide valve into the plunger operation side opening part of the injection cylinder. (B) It is a figure which shows the state which moved the intermediate | middle slide valve to the chemical | medical solution surface. (C) It is a figure which shows the state which filled the 2nd liquid. (D) It is a figure which shows the state which inserted the plunger sliding valve into the plunger operation side opening part of the injection cylinder. (E) It is a figure which shows the state which moved the plunger sliding valve to the chemical liquid surface.

FIG. 12 is a diagram illustrating a filling method of an embodiment using a two-liquid type serial sequential dispensing syringe having a slide valve type intermediate slide valve as an intermediate slide valve. (A) It is a figure which shows the kit formulation B which concerns on this invention. (B) It is a figure which shows the state which attached the injection needle and the plunger operation part to the kit formulation B. (C) It is a model diagram showing a state in which the inside of the syringe is sucked to reduce the pressure. (D) It is a diagram showing a state in which water vapor is supplied while the inside of an injection or the like is being suctioned and a drug solution is filled. (E) It is a figure which shows the state which inserted the intermediate slide valve in the plunger operation side opening part of the injection cylinder. (F) It is a figure which shows the state which moved the intermediate | middle slide valve to the chemical | medical solution surface.

[Explanation of symbols]

1 injection cylinder 1a injection needle connection part 1c communication passage 2 plunger slide valve 2a plunger operation part 3 intermediate slide valve 3a annular lip 3b holding part 111 4 cap 5 first drug solution 6 second drug solution 7 injection needle d 10 ( Introducing pipe 11 for introducing water-soluble gas Chemical liquid introducing pipe H1 Sliding valve body of intermediate sliding valve Hd Slide valve type intermediate sliding valve

Claims (6)

[Claims] 1. An intermediate slide valve having one or more intermediate slide valves inside an injection cylinder, the injection needle mounting portion being tightly plugged, and the intermediate slide valve located closest to the injection cylinder needle side of the intermediate slide valves. Regarding a method for manufacturing a syringe-type kit preparation in which a space in the needle side of a syringe is filled with a drug solution, a plunger of a syringe in which the inside is in a reduced pressure atmosphere after injecting the drug solution into a syringe with a sealing plug on a needle mounting part In the method for producing a syringe-type kit preparation in which an intermediate slide valve is inserted into the operation side opening and then the intermediate slide valve is moved to or near the liquid surface of the liquid medicine, the reduced pressure atmosphere is a gas soluble in water. A method for producing a syringe-type kit preparation, characterized in that the atmosphere is rich in reduced pressure. 2. The method according to claim 1, wherein the injection of the medicinal solution into the injection cylinder having the injection needle mounting portion sealed is performed under a reduced pressure atmosphere rich in water-soluble gas. Method for manufacturing syringe-type kit preparation. 3. The method for producing a syringe type kit preparation according to claim 1, wherein a degassed drug solution is used as the drug solution. 4. The reduced pressure atmosphere inside the syringe barrel is formed by being sucked from the plunger operation side opening of the syringe barrel, and the water-soluble gas is supplied to the vicinity of the liquid level of the drug solution inside the syringe barrel. The method for producing a syringe-type kit preparation according to claim 1, wherein 5. The method for producing a syringe-type kit preparation according to claim 1, wherein the water-soluble gas is carbon dioxide or water vapor. 6. An intermediate slide valve having one or more intermediate slide valves inside the syringe barrel, the injection needle mounting portion being tightly plugged, and the intermediate slide valve located closest to the syringe barrel needle side among the intermediate slide valves. Regarding a syringe-type kit preparation in which the space inside the syringe needle is filled with a drug solution, after the drug solution is injected into a syringe with a tightly plugged injection needle mounting part, the plunger operation side opening of the syringe has a reduced pressure inside In the syringe-type kit preparation produced by the step of moving the intermediate slide valve to the liquid surface or near the liquid surface after inserting the intermediate slide valve into the part, the reduced pressure atmosphere is a gas soluble in water. A syringe-type kit preparation characterized by a rich reduced pressure atmosphere.