JPS6334480A - Freeze-drying method and device - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [Field of Application of the Invention] The present invention relates to a method and apparatus for continuously drying frozen processed liquids such as foods and medicines, and particularly relates to a method and apparatus for drying frozen chemical liquids. Regarding equipment.

[Prior Art] Conventionally, drying technology using vacuum freeze-drying has been used to reduce product quality deterioration due to drying. In this method, the drug was put into a container such as an ampoule or a vial (hereinafter simply referred to as a "container"), and the container was dried by evacuating the interior of the freeze-drying chamber.

That is, as a freeze-drying warehouse, the outer shell of the wholesaler is generally a vacuum pressure-resistant container, the interior is formed into a shelf type, and the trays containing ampoules and vials are placed on the shelves. Freeze-drying jIIi is then stored in vacuum freeze-drying 1 for a predetermined period of time.
During storage, the medicine in the container was dried by sublimation, and the water vapor in the container was exhausted by a vacuum pump.

In addition, as a small-scale freeze-vacuum drying technique, as shown in FIG.
It is disclosed that this is frozen and attached to the manifold pipe 43 via the rubber pipe 42 (511 Pharmaceutical Engineering, Pharmaceutical Development 7!1m-ZaX, Publication date: March 1, 1970, Publisher:
Jijinshokan Co., Ltd.), the manifold 43 is evacuated in advance with the vacuum pump 45 with the cock 44 closed,
After attaching the ampoule 41, open the cock 44.

Note that there is a cock 46 between the manifold 43 and the vacuum pump 45.
．． A dehumidifying device 48 is connected via 47. Further, reference numeral 49.50 is a vacuum gauge.

[Contents of the Prior Art] In order to supply sublimation heat during drying of drugs in containers in a freeze-drying chamber as described above, it is necessary to supply heat of sublimation through a vacuum layer to the containers placed on a shelf in the freeze-drying chamber. It is the center of heat transfer. Therefore, in consideration of replenishment of heat suppression, that is, heat transfer by convection, it is necessary to suppress the degree of vacuum in the freeze-drying J11- to some extent.

Furthermore, when using a large freeze-drying chamber, drying conditions vary depending on the location within the chamber, making it impossible to achieve uniform drying throughout, and the drying time is set for the slowest drying container. This is because conditions such as heating and heat transfer are different between the center and the outer periphery of shelves and trays in the freeze-drying warehouse, and heat supply to each individual container is not constant, resulting in variations.

Furthermore, as vials and ampoules need to be stored in the freeze-drying warehouse for long periods of time for drying, we have installed one each of a filling machine, a sealing machine, and a packaging line on the continuous line for product manufacturing. In the case of continuous operation, it is necessary to provide multiple freeze drying devices or increase the size of the freeze drying devices. This makes it difficult to handle with subsequent processes, increases equipment costs, increases listing space, and also increases power costs due to long drying times and heating and cooling of equipment and heat medium. ! There was one question.

Furthermore, long drying times minimize the chance of dust contamination. α
The taste is also not pleasant.

Furthermore, since the storage capacity in the freeze-drying warehouse is constant and the size of the container is determined by the size of the container, the productivity of large containers such as drip bottles will be extremely low.

On the other hand, the technique shown in FIG.
After that, the cock 44 formed in the manifold 43 is opened to dry the material inside the ampoule 41. Although it is effective for small-scale freeze-vacuum drying, it is not possible to dry the ampoule continuously. I can't do anything.

[5P, ljl or problems to be solved] The present invention
The present invention was developed in view of the above-mentioned problems, and aims to provide a method and apparatus for continuously drying drugs in containers such as vials and ampoules in vacuum freeze-drying without using a freeze-drying chamber.

[IF! Means for Solving Problem 1] In order to solve problem 1, the present invention has a method of continuously vacuuming and drying a container containing a frozen processing liquid (medicine).

Furthermore, the apparatus used in the above method includes a container containing a frozen processing liquid (drug) and a means for continuously drying the processing liquid (drug) in the container, and continuously dries the processing liquid (drug). The means includes a means for continuously holding the container, a vacuum system connected to the container holding means by a tube via a valve, and a vacuum system provided in the middle of the tube. ! The configuration is formed from the jt position.

[Operation] Next, the operation of the apparatus according to the present invention will be explained based on the first "J!" example.

As shown in FIG. 1 which is a first embodiment, a medicine M etc. is put into a tome container 10, and the container 10 containing the medicine M is frozen. The container is moved under the holter l by the container supply device and placed at the opening 1a of the holder l. When the container lO comes to the opening 1a of the holder l, the hartz 2 is opened, By the vacuum device 4, the pipe body 4a, the dehumidifier 3. Since the tube body 2a is in a vacuum state, the container l
The opening 10a of the holder L is sucked and brought into close contact with the opening 1a of the holder L. At this time, put the packing lb inside the holder 1.
is formed, so that the packing 1b and the upper end surface of the container are in close contact with each other. Or the gasket l on the inner end of holder 1.
C and Yomushi shoulder are in close contact.

In this way, under the vacuum condition, the moisture in the medicine M in the container 10 is sublimated, and the moisture is removed by the dehumidifier 3 and discharged.

When the drying of the drug M is completed, the vacuum inside the container 10 is released by closing the valve 2 and opening an auxiliary valve (not shown). The HARTZ 2 and the auxiliary valves are controlled by electricity, air pressure, or the like by a control device (not shown).

In this way, the container itself can be used for freeze-drying, and drying can be accomplished without using a conventional large-scale freeze-drying cabinet. Therefore, it is possible to solve the above-mentioned problems using a freeze-drying oven.

In addition, since the container holder 1 is configured to directly adsorb the container 10, and the vacuum state inside the container 10 can be directly controlled by the valve 2 and the auxiliary Harz (not shown), the container 10 can be vacuum-dried continuously. can. Note that the auxiliary valve as a means for removing the container described in this embodiment is not necessarily essential to the present invention.

[Examples] Examples of the present invention will be described below with reference to the drawings. however,
Of course, the number, size, material, shape, arrangement, etc. of the component parts described or illustrated in the following description of the examples, which are not the gist of the present invention, limit the present invention. It has no purpose and is merely an illustrative example.

FIG. 1 is a schematic diagram showing a first embodiment of the present invention.

As shown in the figure, the vacuum freeze-drying method and apparatus shown in this example include a container 10 containing a frozen drug (medicinal solution M in this example) and a means for drying the frozen drug solution M in the container IO. The drying device as a means for drying the medicinal solution M in the container is composed of a container holder 1 which is a means for continuously holding the container 10, a vacuum valve 2, a dehumidifier 3, a vacuum device 4, and the like.

The container 10 in this example consists of a glass bottle, and the container 10
The container holder 1 that holds the opening la? : It has a cylindrical shape with an angle of fn. The container holder l is connected to the tube body 2a via the vacuum valve 2. Further, a gasket lb is formed in the opening la of the container holder l to make close contact with the upper end surface of the container IO.

A tube body (not shown) communicating with the atmosphere is formed at a desired location of the vacuum valve 2 and the container holder l, and the tube body is also provided with an auxiliary valve (not shown). The vacuum valve 2 and the auxiliary valve are operated electrically or pneumatically by a control device (not shown).

The tube body 2a is a dehumidifying bag g! 13, and the dehumidifying device 3 is connected to a vacuum device M4 via a tube body 4a.

Note that the dehumidifying bag 6 may be an electrical device using a refrigerant, or may be subjected to chemical moisture absorption treatment using a material such as phosphorus pentoxide.

Fig. 2 shows the second embodiment, which is a rotary type continuous freeze drying apparatus, Fig. 2 (A) is a schematic diagram explaining the packaging configuration of this example, and Fig. 2 (B) is a FIG. 3 is a schematic diagram showing the plane of the distributor;

As shown in the figure, the continuous vacuum freeze-drying method and apparatus in this example dry a container 29 containing a frozen drug (medicinal solution in this example) M and the frozen drug solution M in the container 29. The continuous freeze-drying device 20 consists of a container holder 22, which is a means for continuously holding the container 29, and a drying device fi20, which is a means to dry the medicine M in the container. , dehumidifier 2
4, a vacuum device 25, a rotary seal device 26, etc.

The distributor 21 has various tube bodies 21a extending radially, and a holder 22 is formed at the tip of the extended tube body 21a via a vacuum valve 23, and a container 29 is held by the holder 22. It looks like this.

The container holter 22 in this example has a cylindrical shape with an opening 22a for holding a container 29 made of a glass bottle. A gasket 22b is formed in the opening 22a of the holder 22 to make close contact with the upper end surface of the container.

Further, a tube (not shown) communicating with the atmosphere is formed at a desired location on the vacuum Harz 23 and the container holder 22, and an auxiliary valve (not shown) is provided in the tube. The vacuum valve 23 and the auxiliary valve are operated electrically or pneumatically by a control device (not shown).

The distributor 21 is of a rotary type, and the distributor 21
is rotated by rotating the rotary sealing device 26 at a predetermined speed using a rotating device (not shown), a chain, a belt, etc.

The rotary seal device 26 includes a pipe body 27, a mechanical seal,
It is kept airtight by a well-known sealing device such as a crand seal or a magnetic fluid seal.

It is connected to a dehumidifier 24 via a tube 27, and the dehumidifier 24 is communicated with a vacuum device 25 via a tube 28. The dehumidifying device 24 generally uses a cold trap that connects the plate and an external cooling device with a pipe and can maintain the plate at 50° C. or lower.

Further, around the rotary type distributor 21, a container 29 is provided.
A supply device, a heating device, etc. (none of which are shown) are formed. Different heating devices are used from the supply point of the container 29 indicated by the arrow X in FIG. 2(B) to the point B (distance β) and from the point B to the point γ C, respectively. For example, a heating device using warm air or a heater is placed at distance β (between the container supply point and symbol B), and a heating device using electromagnetic waves, microwaves, etc. is placed at distance γ (between symbol BC). It is desirable to do so.

The location marked by symbol B may be placed anywhere, and the distance β and distance γ do not need to be separated at the location marked by symbol B, but may overlap each other.Furthermore, the distance 2!29 is separated at the location marked by symbol C. It is supposed to be done.

Next, the operation of this embodiment will be explained. .

In FIG. 2, a drug solution M is stored in a container 29, and the drug solution M in the container 29 is frozen by a freezing device (not shown).

The medicinal solution M in the container 29 may be frozen as it is, as in this example, or it may be frozen while rotating the container 29 at high speed, as shown in FIG. 2(C).
It is possible to freeze the chemical solution M with it attached to the inner wall. In this way, the area of the chemical solution can be increased and the drying time can be shortened.

The container 29 containing the frozen chemical solution M is supplied from a position below the holder 22 of the distributor 21 by an elevator-type container supply device (not shown) and is attracted to the holder 22, which is attached to a rotary sealing device. 26. A dehumidifying device 24 through a pipe body 27. It is connected to a vacuum device 25 via a tube body 28.

Note that whether or not the container 29 is normally suctioned is detected on the spot at the same time as the container 29 is suctioned, and in the case of poor suction, the container 29 is removed.

In this example, the distributor 21 rotates clockwise, but in the process of rotating from the container supply point (indicated by the arrow Dry by drying. Generally, it is preferable to use warm air or an infrared heater for primary drying, and for secondary drying to use microwaves or the like, which can remove residual moisture.

When the 0 point is reached (that is, after the drying is completed), the distributor 2
1 and the holder 22, and open an auxiliary valve (not shown) to release the vacuum inside the holder 22 and release the container 29 that is in close contact with the holder 22.

As described above, the container 29 can be removed manually or mechanically without using an auxiliary valve. For example, as shown in FIG. A stopper S is formed on the stopper S.
The container 29 may be hit by the container 29, the container 29 is tilted, the vacuum state inside the container is released, and the container 29 falls onto a table, conveyor, etc. K due to its own weight.

Thereafter, the capping material is sealed using a capping machine (not shown) and moved on to the next process.

The mouths of the containers in which the drug is frozen are sequentially brought into contact with the removable freezing vacuum system fittings to evacuate the inside of the container, and heat is supplied from the container's peripheral wall to rapidly sublimate the water in the drug. After drying, the dried containers are removed, new frozen containers are sequentially connected to the freezing vacuum system cap, and the above operations are repeated to sequentially and continuously store containers containing lyophilized products. can be manufactured.

By using a continuous freeze-drying apparatus like the one in this example, it becomes possible to carry out continuous operations from washing and drying containers to filling and freeze-drying the medicinal solution to sealing and packaging.

In this way, drug bottles,
Since it becomes possible to freeze-dry ampoules directly and process them continuously, it is possible to solve the conventional problems arising from drying techniques using freeze-drying chambers.

FIG. 3 shows a freeze-drying apparatus showing another embodiment, FIG. 3(A) is a schematic diagram explaining the configuration of this embodiment, and FIG. 3(B) is a schematic diagram showing the plane of the distributor. be. In this example, the same operations as in the second embodiment shown in FIG.

In this example, it is possible to process multiple containers instead of the container holder from the branch pipe from the distributor in the second embodiment, and the initial exhaust for adsorbing the containers is separated. This figure shows the method for discharging the air out of the vacuum system.

The continuous freeze-drying apparatus 30 in this example includes a distributor 31, a container holder 32, and a vacuum valve 33a.

33b, 33c, a cold trap and a cooling device (none of which are shown), a vacuum device 34, a rotary seal device 35, and the like.

The distributor 31 in this example is internally divided into two chambers,
One chamber 31b communicates with a vacuum device (vacuum pump) 34 via a rotary seal 31c and a vacuum pipe 34a, and the other chamber 31a communicates with a cold trap via a rotary seal device 35 and a tube body 35a.

Further, the distributor 31 and the holder 32 are connected to two vacuum pipes 3
6a and 36b, and a valve 33a is formed in the tube 36a, and a valve 33b is formed in the tube 36b, respectively. The tube body 36a is the distributor 31
The chamber 31a and the tube body 36b communicate with the chamber 31b of the distributor 31.

Further, a valve 33c is formed at the end of the holder 32 opposite to the container suction port 32a.

In the holder 32 in this example, the opening end is divided into four branches, and four container suction ports 32a are formed. Further, a container needle stand 37 is formed at the bottom of the holder 32.
It is configured to rise E to the suction position.

The distributor 31 has sprockets, pulleys, etc. attached around the rotary seal device 35, and is rotated by a drive device (not shown) via a chain, belt, etc.

Incidentally, reference numeral 40 is a heating device, which in this example also performs secondary drying and secondary drying as explained in the embodiment shown in FIG. 2 above.

Next, the operation in this example will be explained.

The pre-frozen medicine container 39 is transferred to the container supply device 213.
8 to the container upper sheath 2137. Container top exterior 2
137 consists of a multi-row container alignment device, which aligns the containers 39 at intervals between the suction ports 32a of the container holder 32, moves at the same speed as the rotation speed of the container holter 32 of the distributor 31, It is lifted up to the suction port 32a, moves along with the container halter 32 halfway to the suction confirmation position of the container 39, which will be described next, and then returns to its original position. Further, when the upper end surface of the container 39 rises to the suction port 32a, the suction valve 33b is opened, and the container 39 is suctioned and brought into close contact with the container 39, and the inside of the container 39 is evacuated.

Container holter 32 after advancing one pitch (Fig. 3 (
If the degree of vacuum in the distributor 31 is above a certain level at the point marked in B), the suction valve 33b is closed and the main valve 33a is opened. When the degree of vacuum within the distributor 31 does not increase due to insufficient adsorption or damage to the container 39, the valves 33a and 33b are closed, and the container 39 is removed using the valve 33c. The detached container 39 is removed from the system.

In this example, the suction state of the container 39 is detected after advancing one pitch (at the point marked with the symbol), or as in the second embodiment described above, the suction state of the container 39 is detected on the spot at the same time as the suction of the container 39. It can also be configured. In this way, the device can be simplified.

Note that the container adsorption method and the container lifting device are not limited to the above-mentioned example, and a device that matches this may be used by rotating the distributor intermittently.

The second drying is performed until the distributor 31 reaches a position of about 1/2 to 3/4 rotation (point E). - For the next drying, heating means such as hot air or infrared rays are used.

Next, perform secondary drying from before point E to the separation point E point.
Secondary drying uses four stages of heating using microwaves or the like. These heating means are similar to those in the embodiment shown in FIG. 2 above.

Then, the main harness 33a is closed at the container detachment section F.

Open the valve 33c to remove the container 39 and remove the valve 33.
Close c. Then, the container is suctioned from the container supply bag, which is the first step.

The detached container 39 is immediately sealed and moved to the next step.

In this way, each of the above steps is performed sequentially.

By providing a large number of distributor holders or increasing the number of adsorption containers per holder as in this example, the throughput can be easily increased.

As described above, the second and third embodiments have the following remarkable effects.

Compared to powdered injections, it is possible to produce lyophilized injections with better quality such as solubility, fine particles, and filling accuracy than ever before, and at a cost that is equal to or lower than the formulation cost of powdered injections. Ru.

Since it can be freeze-dried immediately after filling, it is suitable for unstable drugs such as heat-sensitive pharmaceuticals, vaccines, biological preparations, etc.

By using electromagnetic waves, microwaves, etc., it is possible to dry the dried drug part without heating it.

Since no heat is applied to the drug part in this way, it is suitable for heat-sensitive medicines. Furthermore, various problems such as handling associated with the half-capping manufacturing method of rubber stoppers, which is generally practiced in freeze-drying vial filling, are solved.

[Effects of the Invention] The present invention, configured as described above, provides a method and an apparatus for continuously drying a drug in a container such as a vial or an ampoule in vacuum freeze-drying without using a freeze-drying chamber. I can do that.

[Brief explanation of drawings]

The figures show the method and apparatus of the present invention, FIG. 1 is a schematic explanatory diagram showing the first embodiment of the invention, and FIG. 2 shows the continuous freeze-drying method and apparatus according to the second embodiment. Figure 2 (A) is a schematic diagram illustrating the configuration of the second embodiment, Figure 2 (B) is a schematic diagram showing the front side of the distributor, and Figure 2 (C) is a schematic diagram illustrating the method of freezing the processing liquid in the container. 2(D) is a partial sectional view showing an example of container removal; FIG. 3 is a continuous freeze-drying method and apparatus showing a third embodiment; FIG. (A
) is a schematic diagram for explaining the configuration, FIG. 3(B) is a schematic diagram showing the front side of the distributor, and FIG. 4 is a conventional example.

Claims (1)

[Scope of Claims] 1. A freeze-drying method characterized by continuously drying a container containing a frozen processing liquid under vacuum. 2. It consists of a container containing frozen processing liquid and a means for continuously drying the processing liquid in the container, and the means for continuously drying the processing liquid consists of a means for continuously holding the container, and a means for continuously drying the processing liquid in the container. A freeze-drying apparatus comprising: a vacuum device connected to a container holding means by a tube via a valve; and a dehumidifier disposed in the middle of the tube.