RU2685412C2 - Method for washing sevoflurane container and method for storing sevoflurane - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: group of inventions relates to drug storage. Method of flushing a container for storing sevoflurane involves the following stages: creating a condition in which the sevoflurane vapour is present in the storage container; contacting a liquid consisting of a substance containing water molecules, which are 99.9 wt. % of said substance, with an interior wall of a sevoflurane storage container and draining the sevoflurane-containing liquid from the storage container until it remains a liquid; and introducing drying gas into the storage container in order to remove the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container. Also disclosed is a version of a method for washing a container for storing sevoflurane, a method of producing a pharmaceutical product which is sevoflurane, as well as a method of storing sevoflurane.EFFECT: group of inventions enables efficient washing of used container for storage of sevoflurane by means of inexpensive liquid containing water as main component, in particular, the flushing can be performed to the extent that essentially neither sevoflurane nor its analogues can be detected in the storage container.14 cl, 4 dwg, 4 ex

Description

TECHNICAL FIELD TO WHICH INVENTION RELATES.

[0001]

The present invention relates to a method for washing a container for storing a drug, and in particular fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane), which is widely used as an inhalation anesthetic, as well as to a method for storing sevoflurana.

BACKGROUND

[0002]

Fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane) is widely used as a safe inhalation anesthetic. As disclosed in Patent Document 1 (US Patent No. 4250334), sevoflurane can be synthesized by adding concentrated sulfuric acid and hydrogen fluoride to paraformaldehyde, heating the resulting reaction mixture and adding to this mixture dropwise 1,1,1,3,3,3 -hexafluoroisopropyl alcohol (HFIP). The substance of interest (that is, sevoflurane) can be collected together with the unreacted substance (for example, HFIP) by collecting the gas generated in the reaction system.

[0003]

In the above synthesis reaction of sevoflurane, various by-products are produced. These by-products can be separated or removed together with an unreacted substance (for example, HFIP) through, for example, the stages of contacting sevoflurane with a “Bronsted acid, such as concentrated sulfuric acid, a Lewis acid or an acid immobilized to a resin, etc.” ( see Patent Document 2: Japanese Patent No. 2786106), contacting sevoflurane with a “basic aqueous solution, such as an aqueous solution of sodium hydroxide” (see Patent Document 3: Japanese Patent No. 4087488), and “distilling and / or purifying sowing flurana decomposition in the presence of an inhibitor such as sodium hydrogen phosphate "(see Patent Document 4:. № Japanese Patent 2786108). Accordingly, high purity sevoflurane can be obtained. It is also known that the stability of sevoflurane during long-term storage can be significantly improved by adding a small amount of water (from 206 ppm to 1,400 ppm) to sevoflurane thus purified (high purity sevoflurane) (see Patent Document 5: Japanese Patent No. 3664648).

[0004]

Meanwhile, Patent Document 6 (Japanese Patent No. 3183520) discloses that a container made of glass, plastic, steel, etc. can be used as a container for storing sevoflurane. Patent Document 7 (Japanese Patent No. 3524060) discloses that for such a container, specific plastic elements of polyethylene naphthalate, polymethylpentene, polypropylene, polystyrene, etc., are preferably used, and Patent Document 8 (Japanese Patent No. 5801024) discloses that as a container An aluminum container with an inert lacquer or enamel coating can preferably be used for storage.

SUMMARY OF INVENTION

TECHNICAL PROBLEM

[0005]

Since sevoflurane is an ether in the form of a volatile liquid, a sealed container is used as a container for storing sevoflurane.

[0006]

In particular, it is generally accepted to use a large hermetically sealed container (for example, a container with an internal volume of 500 dm ³ ) as a storage container for deliveries and transportation of sevoflurane as an “active pharmaceutical ingredient”. In fact, such a large hermetically sealed container is very expensive and therefore must be reused for a number of batches. In particular, sevoflurane is produced as an active pharmaceutical ingredient, placed in such a large hermetically sealed container, and then shipped. The consumer performs the stage of sevoflurane consumption (also called the stage of assessing the quality of sevoflurane as a medicine and the distribution of sevoflurane as a medicine in glass ampoules, etc.) and then returns the storage container containing a small amount of sevoflurane to the manufacturer. The manufacturer fills the container with newly synthesized sevoflurane for a new batch and ships the product again.

[0007]

Here, if sevoflurane is supplied as an active pharmaceutical ingredient, the hermetically sealed container is filled with sevoflurane, which is a significant part of the active pharmaceutical ingredient, which preferably means that the gas phase (i.e., the void in the container) is filled with an inert gas (for example, gaseous nitrogen). More preferably, based on disclosure of Patent Document 5, a small amount of water (from 206 to 1400 ppm) is added as a stabilizer to sevoflurane, so that sevoflurane is in conditions with improved stability. In such strictly controlled conditions, sevoflurane is very stable, and therefore it is not a substance that can easily decompose.

[0008]

However, after sevoflurane undergoes a consumption stage, a small amount of sevoflurane in liquid or gaseous form remains in the container for storing sevoflurane and coexists with a gas phase (inert gas or air) with a relatively large volume until the sevoflurane storage container returned to the manufacturer. After sevoflurane remains in such conditions for a long period of time, it may behave differently from sevoflurane in the usual state, “placed in a hermetically sealed container.” In particular, the authors of the present invention found that if the sevoflurane in the liquid phase was in contact with a large amount of drying gas for a long period of time, the moisture in the sevoflurane preferably evaporates, which leads to a different behavior of the liquid sevoflurane due to a gradual decrease in moisture content (see Reference Example 1 below).

[0009]

Meanwhile, as disclosed in Patent Document 5 and described in the Examples below, when sevoflurane is under harsh conditions, while its moisture content is very low, a part of sevoflurane can be converted to an analog compound, which is called "polyester" (usually " polyester 1 "or" polyester 2 ", which are shown below).

[0010]

(CF ₃ ) ₂ CHO-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 1>

1,1,1,3,3,3-hexafluoro-2 - [[2,2,2-trifluoro-1- (trifluoromethyl) ethoxy] methoxy] propane

(CF ₃ ) ₂ CHO-CH ₂ -O-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 2>

2,2 '- [Oxybis (methylenoxy)] bis [1,1,1,3,3,3-hexafluoropropane]

[0011]

Since sevoflurane is a drug (anesthetic), such a conversion product should not be contained in sevoflurane for the next batch, even if the content of this conversion product is very small. It should be noted that the “Official monograph on sevoflurane” of the seventeenth Japanese Pharmacopoeia (JP17) on p. 996 indicates that the concentration based on the peak area of gas chromatography for each impurity, which differs from sevoflurane and hexafluoroisopropyl methyl ether in the product of sevoflurane, should not exceed 25 parts per million for each compound, and the total concentration of impurities should not exceed 50 parts per million. In addition to this, it is believed that such "impurities" are mainly byproducts formed during the synthesis of sevoflurane and the purification steps. Thus, it is assumed that such impurities are not compounds that are formed from sevoflurane of the previous batch in a storage container.

[0012]

In addition, it may take a relatively long period of time (for example, 6 months) in order to return the container for storage to the manufacturer due to problems with transportation after the “consumption stage” has completed.

[0013]

Sevoflurane is initially a very stable compound. However, in view of the aforementioned circumstances, it may not be possible to prevent undesirable side reactions after the completion of the “consumption stage” until the container is returned. For this reason, in order to confidently guarantee the quality of sevoflurane, when the manufacturer refills the sevoflurane container for a new batch, it is extremely necessary to rinse the inside of the container thoroughly in order to completely wash away the sevoflurane remaining in the container from the previous batch.

[0014]

Incidentally, as a method for washing the inside of a container for a liquid (such as a liquid compound or a liquid composition), washing with “a liquid identical to a stored liquid” is often performed. Such a washing operation is commonly referred to as “rinsing,” which is widely used in methods for washing containers, in particular for solution analysis. In the case of sevoflurane, as might be expected, based on the fact that each of the above analog compounds (polyester 1 and polyester 2) have a common basic structure with sevoflurane, these analogs have a high affinity for sevoflurane. Therefore, the authors of the present invention have suggested that rinsing with “purified sevoflurane” (also called “rinsing with sevoflurane”) is particularly preferred. This washing method has been used for many years in production.

[0015]

However, in order to perform “rinsing with sevoflurane” until complete removal of impurities and confidently ensure such removal, in principle it is necessary to repeat “rinsing with sevoflurane” many times. This inevitably causes an increase in the consumption of "sevoflurane". Since “sevoflurane” is an expensive product, “rinsing with sevoflurane” leads to inappropriate use of resources, which is an economically unfavorable factor. Thus, there is a need to develop a washing method that could replace such a rinsing method.

[0016]

In most cases, a “method of using an organic solvent as a washing liquid” is known as a method for washing a container. However, sevoflurane is an “inhalation anesthetic”, and therefore it should not be mixed with even a small amount of organic solvent. Examples of solvents having high affinity for sevoflurane and its analogs include methanol, acetone and diethyl ether. These examples are solvents having a relatively low boiling point. Such solvents can be considered easily removable by drying. However, in practice it is quite difficult to wash the container for storing sevoflurane using the solvents described above. In particular, it is actually possible to remove a significant portion of such an organic solvent after washing the storage container with this solvent and supplying hot air to the storage container or creating a vacuum in the storage container. If the container that has been treated with such drying agents is filled with sevoflurane from the new batch, a small peak of solvent can be found together with the peak of sevoflurane on the gas chromatogram (for more details see “Comparative Example 1” below). If an organic solvent is detected in the new sevoflurane, the corresponding product will be rejected.

[0017]

Thus, using the aforementioned organic solvents as a washing liquid for a “pharmaceutical product of sevoflurane,” which should not contain impurities even at the level of parts per million, can increase the cost of quality control. Thus, the use of such solvents has never been preferred.

[0018]

In view of the above, the object of the present invention is to propose a new method for washing the storage container of sevoflurane.

SOLUTION TO THE PROBLEM

[0019]

As a result of intensive research to solve the problem, the authors of the present invention have found an excellent method for washing the used “container for storing sevoflurane” with the help of “liquid containing water as the main component”. In particular, the present invention relates to a method for washing a used "container for storage of sevoflurane", comprising the steps of:

creating a state in which at least a pair of sevoflurane is present in the storage container (stage A);

contacting water containing the main component with the inner wall of the storage container for sevoflurane in a state in which sevoflurane vapor is present in the storage container after stage A, and draining the liquid from the storage container as long as it remains liquid (stage B) ; and

the introduction of the drying gas in the storage container in order to drain the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after stage B (stage C).

[0020]

In accordance with the present invention, a “storage container for sevoflurane”, which is an object for washing (i.e., the “storage container for sevoflurane" used above) is a storage container for sevoflurane, which is reused for multiple batches, and which was subjected to consumption stages at least part of sevoflurane placed in a storage container from the previous batch (usually, essentially all or all of sevoflurane placed in the container).

[0021]

The present invention is characterized by the “Stage A” described above, that is, the stage of creating such a state in which at least the sevoflurane vapors are present in the storage container. By performing “Stage A”, it is possible to continuously maintain the inner wall of the sevoflurane storage container in contact with the sevoflurane molecules, thereby allowing for efficient washing with “liquid containing water as the main component” at stage B.

[0022]

In particular, an attempt was made to allow the container for storing sevoflurane (in particular, its inner wall) to have an affinity for the molecules of sevoflurane using “stage A”, to ensure contact of “liquid containing water as the main component” with the inner wall of the storage container a condition in which sevoflurane vapors are present in the storage container, in “Stage B,” and then drain the liquid from the storage container. As a result, it was found that washing could be achieved to such an extent that essentially no sevoflurane or hydrophobic “polyester 1 and polyester 2” remain in the washed container (i.e., less than 1 ppm concentration is reached). In addition, it was found that even after repeated reuse of the storage container, sevoflurane, polyester 1 and polyester 2 do not accumulate in the storage container (see “Examples” below).

[0023]

In addition, the authors of the present invention attempted to carry out a washing step corresponding to “stage B”, placing sevoflurane under stringent conditions in the intended manner in a storage container in order to force part of sevoflurane into “polyester 1 and polyether 2”, and preserving the resulting “sevoflurane containing dissolved polyesters in relatively high concentrations "in a storage container. As a result, the authors of the present invention have found that it is possible to wash not only sevoflurane, but also “polyester 1 and polyester 2” from the storage container of sevoflurane using “liquid containing water as the main component” to level below the sensitivity limit of 1 part per million for gas chromatography (FID). In particular, the authors of the present invention have found that it is possible to use a “liquid essentially consisting of water” as a “liquid containing water as a main component” in a particularly preferred manner. Thus, the authors of the present invention have confirmed that sevoflurane can be drained from the system to such an extent that neither sevoflurane nor "polyester 1 and polyester 2" can be detected (to below 1 ppm) by washing the storage container containing “sevoflurane containing polyester 1 and polyester 2 dissolved in it” several times with “liquid essentially consisting of water” as described in the Examples below.

[0024]

Sevoflurane is an ether with a fluorine chain. In addition, sevoflurane is a substance with low polarity, and thus it has a low affinity for water. As disclosed in Patent Document 5, sevoflurane can be mixed with a small amount of water, thereby improving the stability of sevoflurane, which is known as a particular effect. However, the upper limit of the amount of water that can be mixed with sevoflurane is about 1,400 ppm. If the amount of water exceeds this level, water and sevoflurane tend to repel each other strongly.

[0025]

In addition, the “polyester 1 and polyether 2” described above contain more carbon atoms than sevoflurane, and therefore they have enhanced hydrophobic characteristics. Thus, each of polyester 1 and polyester 2 is a substance with greater polarity (stronger hydrophobicity) than sevoflurane.

[0026]

In most cases, “water” is a liquid having a very high polarity (the water dielectric constant is approximately 80), and therefore it has a low affinity for organic compounds (and especially for compounds that have low polarity and contain many carbon atoms). For this reason, it was thought that “water” was obviously an unsuitable washing liquid for washing from sevoflurane and its analogues. In particular, it was believed that when water is used as a washing liquid, sevoflurane, and especially “polyester 1 and polyester 2”, which have lower polarity than sevoflurane, remain on the inner wall of the storage container.

[0027]

However, the authors of the present invention have found that “sevoflurane analogs (polyester 1 and polyester 2)” remaining on the inner wall of the container can be effectively washed off with “water”, which was considered to be an inappropriate washing liquid (and to such an extent that these analogues can be washed down to a level that meets the requirements of quality control of medicines). This was unexpected even for specialists in this field of technology. One possible reason for this is that since sevoflurane can be dissolved in a small amount of water, sevoflurane, remaining as vapors in a container, somehow interacts with the water, allowing the mixture of sevoflurane and water to effectively wash away the polyesters inner wall of the container. (After the authors of the present invention achieved the present invention, they re-examined the bibliography and found that Japanese Patent No. 3612590 discloses that “polyester 1” forms an azeotropic mixture with butanol. In addition, Japanese Patent No. 5244109 discloses an experimental example in which the composition of the organic compound, including “polyester 1, was washed off with water (Example 3); however, the content of“ polyester 1 ”remained unchanged before and after washing with water. Both references simply confirm the fact that“ polyester 1 ”represents It is a substance with a very low affinity for water.)

It should be noted that the used “storage container for sevoflurane” (i.e., the storage container for sevoflurane, which has been subjected to the consumption stage) is usually not exposed to a “hard environment” during the actual introduction of sevoflurane. Therefore, it is believed that sevoflurane in the “used container” is unlikely to be converted into its analogues, such as the “polyester 1 and polyether 2” described above. However, since sevoflurane is used as a drug, quality control should always be carried out for the worst case scenario. In particular, it is essential to completely drain the sevoflurane from the storage container by the time it is filled with sevoflurane from the next batch, even if this sevoflurane is converted to polyester 1 and polyester 2 for some reason. Thus, a flushing agent is necessary in order to completely eliminate the risks associated with the product of sevoflurane and to guarantee the quality of sevoflurane with confidence.

[0028]

The authors of the present invention have found that a “liquid containing water as a main component” and especially a “liquid essentially consisting of water” can preferably be used as a flushing agent, thereby allowing the container to be stably washed many times, ensuring sufficiently This is the quality required for pharmaceutical products. Accordingly, production costs can be significantly reduced compared with regular washing of containers for storage of sevoflurane.

[0029]

In accordance with the present invention, the expression "liquid containing water as the main component" refers to "a single-layer liquid containing 50% by weight or more of water." In particular, such a liquid is preferably either a “liquid forming a single layer consisting of a mixture of water and a non-aqueous liquid” or “a liquid essentially consisting of water”. "Fluid essentially consisting of water" is particularly preferred. Thus, the authors of the present invention have found that even a “liquid essentially consisting of water” can be used to rinse the container so that the washing can be performed to a level comparable to “rinsing with sevoflurane”.

[0030]

The washing operation used in this document is not particularly limited. However, it is preferable to perform this operation by directly injecting a “liquid containing water as the main component” onto the inner wall of the storage container using a spray nozzle. Particularly preferably, the temperature of the liquid was relatively high, from 60 ° C to 90 ° C.

[0031]

The present invention is also characterized by performing the step of introducing the drying gas into the storage container in order to drain the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container (stage C) after the above described step B.

[0032]

Stage C described above allows draining from the container a portion of the “liquid containing water as the main component” used to rinse the storage container for sevoflurane, which sticks to (remains on) the inner wall of the container, together with the drying gas, thereby drying the inner wall of the container. In addition, sevoflurane vapors may remain in the gas phase of the storage container after stage B. However, such sevoflurane vapors may be completely drained from the container by performing stage C. This allows the storage container to be suitable for refilling with new sevoflurane.

[0033]

It is possible to produce a "pharmaceutical product of sevoflurane placed in a container" by performing the stage of filling with sevoflurane from a new batch using a container for storage of sevoflurane subjected to the "stage of washing the container for storage of sevoflurane (first stage)" including the above described stages A - C.

[0034]

In addition, it is possible to stably store the manufactured “pharmaceutical product” at the subsequent “storage stage” (third stage).

[0035]

The present invention is also advantageous for the following reasons. When “rinsing with sevoflurane” is performed without rinsing with “liquid containing water as the main component”, it is necessary to fill the container with sevoflurane from the new batch as soon as possible after “rinsing with sevoflurane” (usually within one month) from the point of view of stage control. The reason for this is that the state in which “a relatively small amount of sevoflurane remains in a large capacity storage container” is more or less different from the state in which “the storage container is filled with a predetermined volume of sevoflurane” when the product is shipped , as mentioned above, and therefore it is preferable not to allow sevoflurane to remain in this state for an unnecessarily long period of time.

[0036]

Thus, if “rinsing with sevoflurane” is performed, the best way from the point of view of quality control is to finish the stage of filling the container with sevoflurane from the new lot as soon as the rinsing is completed.

[0037]

In the meantime, when the washing with “liquid containing water as the main component” is performed in accordance with the present invention, there is essentially no sevoflurane or by-product in the container. In this case, even if the container is filled with sevoflurane from a new batch after the container has been left for a long period of time after the washing stage has been completed (for example, for 6 months), no problems will arise. In particular, it is also possible to “rinse the container” and “fill the container with sevoflurane from a new lot” at different times, which significantly increases the degree of freedom for each stage.

[0038]

As mentioned above, the authors of the present invention have found that the container for storing sevoflurane can be washed using “liquid containing water as the main component”, which turned out to be surprisingly advantageous. This led to the completion of the inventions of the present patent application.

[0039]

In particular, the present invention encompasses the following inventions.

[0040]

[Invention 1]

A method for washing a storage container for sevoflurane, in which

the storage container is a storage container for sevoflurane, which is reused for multiple batches, and which has been subjected to the consumption stage of at least part of sevoflurane from the previous batch, placed in a storage container,

moreover, this method comprises the steps:

creating a state in which at least a pair of sevoflurane is present in the storage container (stage A);

contacting water containing the main component with the inner wall of the storage container for sevoflurane in a state in which sevoflurane vapor is present in the storage container after stage A, and draining the liquid from the storage container as long as it remains liquid (stage B) ; and

the introduction of the drying gas in the storage container in order to drain the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after stage B (stage C).

[0041]

[Invention 2]

The washing method in accordance with the Invention 1, in which the state in which at least the sevoflurane vapors are present in the storage container at stage A, is a state that is achieved by consuming essentially all of the liquid sevoflurane from the storage container at the consumption stage of sevoflurane into a storage container from the previous batch, and then hermetically sealed the storage container, allowing at least part of the sevoflurane vapor to remain in the gas phase in the storage container and I.

[0042]

[Invention 3]

The washing method in accordance with the Invention 1, in which the state in which at least sevoflurane vapors are present in the storage container at stage A, is a state that is achieved by consuming part of the liquid sevoflurane from the storage container at the consumption stage of sevoflurane, placed in the container for storage from the previous batch, and then hermetically sealed container for storage.

[0043]

[Invention 4]

A washing method in accordance with any one of the Inventions 1-3, in which a liquid containing water as a main component is a liquid essentially consisting of water.

[0044]

[Invention 5]

A washing method in accordance with any one of Inventions 1 to 4, wherein, in order to ensure contact of a liquid containing water as a main component, with the inner wall of the storage container of sevoflurane in stage B, this liquid is injected directly onto the inner wall of the storage container using the injection means fluid.

[0045]

[Invention 6]

The washing method in accordance with the Invention 5, wherein the temperature of the liquid containing water as the main component, when injected, is from 60 ° C to 90 ° C.

[0046]

[Invention 7]

A washing method in accordance with any one of Inventions 1 to 6, wherein part or all of the inner wall of the storage container is made of at least one material selected from the group consisting of stainless steel, a polymer coating, and glass.

[0047]

[Invention 8]

The washing method in accordance with the Invention 7, in which part or all of the inner wall of the storage container is made of stainless steel.

[0048]

[Invention 9]

The washing method in accordance with any of the Inventions 1 to 8, in which the drying gas in stage C is dry air with a temperature of from 30 ° C to 150 ° C.

[0049]

[Invention 10]

The washing method in accordance with any one of the Inventions 1 to 9, in which step C includes confirming that the drying gas leaving the storage container has a dew point equal to or less than the predetermined temperature.

[0050]

[Invention 11]

A method for washing a storage container for sevoflurane, in which

the storage container is a storage container for sevoflurane, which is reused for multiple batches, and which has been subjected to the consumption stage of at least part of sevoflurane from the previous batch, placed in a storage container,

moreover, this method comprises the steps:

creating a state in which at least the sevoflurane vapor is present in the storage container by sealingly closing the storage container, while allowing at least part of the sevoflurane vapor to remain in the gas phase in the storage container after sevoflurane consumption at the sevoflurane consumption stage, placed to the storage container from the previous batch (stage a);

direct spraying a liquid essentially consisting of water onto the inner wall of the storage container using a spray nozzle in order to ensure contact of this liquid with the inner wall in a state in which sevoflurane vapors are present in the storage container after stage a, and then draining the liquid from the storage container while the liquid remains liquid (stage b); and

injecting drying gas into the storage container in order to drain the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after step b, and also confirming that the dew point of the drying gas leaving the storage container is equal to or lower than the predetermined temperature (stage c),

moreover, as a result of carrying out steps a – c, sevoflurane and its analogues (polyether 1 and polyether 2), described by the following formulas, are essentially not detected in the storage container:

(CF ₃ ) ₂ CHO-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 1>

(CF ₃ ) ₂ CHO-CH ₂ -O-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 2>

[0051]

[Invention 12]

The washing method in accordance with the Invention 11, in which part or all of the inner wall of the storage container is made of stainless steel, and the temperature of the liquid essentially consisting of water is from 60 ° C to 90 ° C.

[0052]

[Invention 13]

The washing method in accordance with any one of the Inventions 1 to 12, in which stage B or stage b includes the step of washing the storage container using purified sevoflurane.

[0053]

[Invention 14]

A method for producing a pharmaceutical product, which is sevoflurane, placed in a storage container, containing filling the storage container, washed using a method in accordance with any one of the Inventions 1 to 13 with sevoflurane from a new batch.

[0054]

[Invention 15]

The washing method in accordance with the Invention 14, in which the liquid composition of sevoflurane, placed in a storage container from a new batch, is analyzed using gas chromatography.

[0055]

[Invention 16]

Pharmaceutical product of sevoflouran placed in a storage container, which is produced using the method in accordance with the Invention 14 or 15.

[0056]

[Invention 17]

A method for storing sevoflurane containing the following steps 1-3:

The 1st stage of washing the container for storage of sevoflurane using the method in accordance with any of the Inventions 1 to 13;

The 2nd stage of filling the storage container with sevoflurane from the new batch after washing; and

The 3rd stage of storage of a container for storing sevofluran after filling it.

USEFUL EFFECTS OF INVENTION

[0057]

The present invention is advantageous in that it is possible to efficiently wash the used “container for storage of sevoflurane” with an inexpensive liquid containing water as the main component. Thus, washing can be performed to such an extent that essentially neither sevoflurane nor its analogues (polyester 1 and polyester 2) can be found in a storage container.

In addition, in accordance with the present invention, it is possible to separately perform the washing step of the storage container and the subsequent filling step of the storage container with sevoflurane, thereby allowing an increase in the degree of freedom for each stage.

BRIEF DESCRIPTION OF THE DRAWINGS

[0058]

[FIG. 1] FIG. 1 illustrates the relationship between a “method for washing a used storage container containing sevoflurane”, a “method for producing a pharmaceutical product sevoflurane placed in a storage container”, and a “method for storing sevoflurane”.

[FIG. 2] FIG. 2 illustrates one preferred embodiment of the “Stage B” in the 1st Stage.

[FIG. 3] FIG. 3 shows a schematic view of the “nozzle <a>” used in the “stage B” in the 1st stage.

[FIG. 4] FIG. 4 illustrates one preferred embodiment of the “Stage C” in the 1st Stage.

DESCRIPTION OF EMBODIMENTS

[0059]

The present invention is described in detail below. The scope of the present invention is not limited to the following descriptions. Therefore, various modifications can be made appropriately in embodiments that differ from the embodiments described below, without departing from the scope and spirit of the present invention.

This description includes part or all of the content disclosed in the description and / or drawings of Japanese patent application No. 2016-215676, which is the priority document of this patent application. In addition, all publications, such as prior art documents, deferred patent applications, patent publications, and other patent literature cited herein, are incorporated herein by reference.

[0060]

Each of the inventions of the present patent application includes the following stages from the 1st to the 3rd (see Invention 17).

1st stage: the stage of washing the “container for storage of sevoflurane” with a “liquid containing water as the main component”

Stage 2: Stage of filling the storage container with sevoflurane from the new batch after completion of Stage 1

3rd stage: the storage stage of a container for storing sevoflurane filled with sevoflurane after the 2nd stage.

[0061]

Among the inventions of the present patent application, the “invention of the washing method” is defined as including the “1st stage” described above as a constituent feature. In particular, the “1st stage” includes the stages from “stage A” to “stage C”.

[0062]

"The invention of the method of production" is defined as including the "1st stage" and "2nd stage" as constituent features.

[0063]

“The invention of the storage method” is defined as including the “1st stage”, “2nd stage” and “3rd stage” described above as constituent features.

[0064]

The above steps are specifically described in order, starting with the “1st Stage”. The constituent features and their combinations in the following embodiments are described as examples. Therefore, the constituent features can be added, omitted, replaced or modified without departing from the scope and spirit of the present invention. In addition, the present invention is not limited to the embodiments described below.

[0065]

[1] Relative to stage 1

Stage 1 is the washing stage of the “container for storage of sevoflurane” with a “liquid containing water as the main component”.

[0066]

[Regarding sevoflurane]

Any sevoflurane product widely used as a general anesthetic can be used as sevoflurane in the present invention. The method of synthesis of sevoflurane is not particularly limited. However, sevoflurane can preferably be used produced by any of the methods disclosed in Patent Documents 1-5.

[0067]

[Regarding "storage container for sevoflurane"]

In accordance with the present invention, a “container for storage of sevoflurane”, which is an object for washing (i.e., a used container for storage of sevoflurane) is a container for storage of sevoflurane, which is reused for multiple batches, in which at least part of sevoflurane placed in a container for storage from the previous batch, was consumed.

[0068]

Sevoflurane is an ether, and thus it is highly volatile. Taking this into account, the storage container must have a structure in which sevoflurane can be stored tightly. The shape or material of the storage container is not particularly limited; however, the container body is preferably made of metal, such as stainless steel. In addition, part or all of the inner wall of the storage container is preferably made of at least one material selected from the group consisting of stainless steel (i.e., iron-nickel-chromium alloy), a polymer coating and glass. In particular, a storage container having an inner wall made of stainless steel or a polymer coating is characterized by high physical strength and chemical durability (corrosion resistance) and is therefore suitable for storing sevoflurane in hermetically sealed conditions. A storage container having an inner wall of stainless steel is particularly preferred because it has a simple structure and very high durability. Particularly preferred examples of stainless steel include austenite-based stainless steel products, known as SUS304, SUS316 and SUS316L.

[0069]

Sevoflurane is in the form of a volatile liquid. For example, its vapor pressure is approximately 0.026 MPa at 25 ° C, approximately 0.041 MPa at 35 ° C, and approximately 0.061 MPa at 45 ° C. When liquid sevoflurane is introduced into a storage container filled with an inert gas (for example, nitrogen), the liquid is usually introduced into the container and this container is sealed, after which part of the liquid gradually evaporates into the gas phase in the storage container. Accordingly, the pressure inside the storage container rises slightly if the temperature does not change, as it happens in most cases. If the ambient temperature decreases significantly after filling, the pressure inside the storage container may become negative (less than 1 atm). Therefore, it is preferable that the container for storing sevoflurane has a structure that is resistant to changes in internal pressure (to increase or decrease). In particular, if the storage container is filled with sevoflurane under such conditions, the internal pressure can vary from about 0.08 MPa to 0.13 MPa. Thus, a “container capable of withstanding an internal pressure (absolute pressure) of 0.17 MPa” would be sufficiently able to cope with such a change in pressure, which is preferable. There is no upper limit to the pressure resistance of the container. However, the use of a “container capable of withstanding an absolute pressure of 0.3 MPa or more” causes a complication of its design and maintenance. In addition, since the internal pressure in the storage container of sevoflurane usually does not exceed 0.3 MPa, in most cases there is no need to use a storage container that can withstand an absolute pressure of 0.3 MPa or more.

[0070]

In accordance with the present invention, the “stage of sevoflurane consumption” is, in particular, a stage, for example, performing a qualitative assessment of sevoflurane placed in a storage container, taking sevoflurane from a storage container and pouring it as a medicine into glass ampoules, etc. . At this “consumption stage,” a siphon tube for sevoflurane intake is inserted outside the storage container into the liquid phase of sevoflurane in the storage container, and an inert gas (eg nitrogen) is introduced into the gas phase of the storage container through another opening, thereby rendering a small pressure on the inside of the storage container. In this way, liquid sevoflurane can be collected through a siphon tube.

[0071]

At the aforementioned “consumption stage”, it is usually but not necessary that the storage container is returned to the manufacturer of sevoflurane after the storage container becomes substantially empty as a result of “consuming” a significant part of the liquid sevoflurane placed in the storage container from the previous batch.

[0072]

The internal volume of the storage container for sevoflurane is not particularly limited. The container for storing sevoflurane can be of a size suitable for transporting an acceptably large amount of sevoflurane. For example, a storage container having an internal volume of from 100 dm ³ to 10,000 dm ³ can be used. Such a container may have a larger internal volume or a smaller internal volume. In accordance with the present invention, a “sevoflurane storage container” having an internal volume of 300 dm ³ to 1000 dm ³ is particularly preferred.

[0073]

[Regarding "liquid containing water as the main component"]

In accordance with the present invention, a “liquid containing water as a main component” used as a detergent may be a “single layer liquid containing 50% by weight or more of water”. In particular, such a liquid is preferably either a “liquid forming a single layer consisting of a mixture of water and a non-aqueous liquid” or “a liquid essentially consisting of water”. "Fluid essentially consisting of water" is particularly preferred.

[0074]

The term "non-aqueous liquid" as used herein means a liquid capable of forming a monolayer liquid when mixed with water (for example, alcohol or acetone). In addition, a liquid that has a low affinity for water, but forms a single-layer liquid when mixed in very small quantities with water, can be used as a “non-aqueous liquid” in the present invention, provided that the liquid composition forms a single-layer liquid. when mixed with water.

[0075]

Examples of the “non-aqueous liquid” include, but are not limited to, known hydrophilic solvents, such as methanol, ethanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, ethylene glycol, trimethylamine and triethylamine. If a liquid mixture is used that contains "water and non-aqueous liquid", the mass of water may be 50% by weight or more, preferably 80% by weight or more, and 90% by weight or more of the total weight of the liquid mixture. It should be noted that when a substance other than sevofluran is mixed as a “non-aqueous liquid” with water to use this mixture as a washing solvent, it is necessary to perform the stage C described below until the “non-aqueous liquid” becomes undetectable. This can create difficulties, since the content of the “non-aqueous liquid” must be established as a verifiable indicator.

[0076]

In view of the foregoing, the authors of the present invention have found that “a liquid essentially consisting of water” can preferably be used as a “liquid containing water as a main component”. Therefore, it is particularly preferable to use the "liquid essentially consisting of water" as the "liquid containing water as the main component" in the 1st stage of the present invention.

[0077]

The type of water used in this document is not particularly limited from a technical point of view. It is possible to appropriately use ordinary tap water, ion exchange water, distilled water, water obtained by reverse osmosis (RO water), and the like. It should be noted that since sevoflurane is a substance that can be used as a medicine, it is preferable to use water containing less impurities. It is especially preferred to use ion exchange water or distilled water. In a particularly preferred embodiment, ion exchange water is used, having an electrical conductivity equal to or lower than a predetermined level of 1 μS / cm, which is obtained by passing water through an ion exchange resin.

[0078]

[Concerning Stage A]

Stage A in the 1st stage is the stage of creating such a state in which at least a pair of sevoflurane is present in the container for storing sevoflurane. The storage container, which is the object to be washed, has been described in detail above. When stage A is performed, the sevoflurane molecules continuously come into contact with the inner wall of the storage container, thereby allowing with certainty to obtain the effects of washing with “liquid containing water as the main component” in the subsequent stage (stage B). In the event that stage A is not performed and the inner wall of the container dries, it becomes difficult to expect a sufficient washing effect, even if the washing is performed using “liquid containing water as the main component” in the subsequent stage (stage B). Thus, stage A plays an important role in the present invention.

[0079]

The means for creating a “state in which at least a pair of sevoflurane is present in the storage container of sevoflurane” is not particularly limited at stage A. This tool is explained below in the variants of the implementation from the 1st to the 3rd.

[0080]

(1) 1st Embodiment

At stage A, the “1st embodiment” corresponds to the method of collecting almost all liquid sevoflurane at the “consumption stage” of sevoflurane placed in a storage container from the previous batch, and then sealing the storage container tightly so as to allow the sevoflurane vapor to remain in the gas phase in storage container. In particular, when almost all liquid sevoflurane is consumed (withdrawn) at the “consumption stage” of sevoflurane, a large amount of sevoflurane vapor still remains in the gas phase in the container. For example, since the vapor pressure of sevoflurane is approximately 0.026 MPa at 25 ° C and atmospheric pressure, when almost all of the sevoflurane present in the liquid phase in a 500 dm ³ container is taken, approximately 1 kg of sevoflurane remains in the gas phase in the container provided that losses of sevoflurane in the gas phase are insignificant.

[0081]

The authors of the present invention have found that the amount of "vapor of sevoflurane in the gas phase" in stage A does not necessarily correspond to the pressure of the saturated vapor. In particular, sevoflurane may be present in the gas phase at a temperature of 25 ° C at a pressure of 0.0026 MPa (10% of the pressure of saturated steam at a temperature of 25 ° C) or more, preferably of 0.010 MPa (40% of the pressure of saturated steam at a temperature of 25 ° C) or more, and more preferably at a pressure of 0.020 MPa (80% of the pressure of saturated steam at 25 ° C) or more.

[0082]

It is usually possible to effectively take sevoflurane from a storage container filled with sevoflurane by inserting a siphon tube into the liquid sevoflurane phase, slightly increasing the pressure inside the container through another opening, and obtaining liquid sevoflurane via the siphon tube due to this pressure increase. When sevoflurane is obtained in this way, even if essentially all liquid sevoflurane is removed, essentially saturated sevoflurane vapor remains in the container. The reason for this is that the specific gravity of sevoflurane vapor is much larger than the specific gravity of air or nitrogen, and therefore, in principle, the sevoflurane vapor remains in the lower part (bottom) of the storage container. Therefore, it is possible to leave “sevoflurane in an amount substantially corresponding to saturated sevoflurane vapors” intact in the storage container by closing the siphon tube immediately (for example, for 5 minutes and preferably for 1 minute) after the stage of consuming sevoflurane, without opening the bottom or entering an inert gas into the container (or it is also possible to hermetically close the storage container immediately after removing the siphon tube). By performing this operation, it is possible with certainty to maintain the above-mentioned “state in which the amount of sevoflurane vapor is present, corresponding to a pressure of 0.0026 MPa (10% of the pressure of saturated sevoflurane vapor) at a temperature of 25 ° C”.

[0083]

(2) 2nd embodiment

Another method for stage A (2nd version of the implementation) is a method of consuming (collecting) part of sevoflurane at the stage of consuming sevoflurane placed in a storage container from the previous batch (in other words, storing part of sevoflurane in liquid form in a storage container), and hermetic sealing of the storage container. This technique allows the "liquid sevoflurane" to remain in the storage container, which leads to the establishment of equilibrium between liquid and vapor. Accordingly, the storage container can be filled with saturated vapors of sevoflurane.

[0084]

In particular, in the above-described embodiment, it is possible to use the method of adjusting the position of the siphon tube inserted into the liquid sevoflurane during the sevoflurane consumption stage in order not to consume (not take) part of the liquid sevoflurane phase, the technique of injecting a predetermined volume of sevoflurane into the container deliberately when confirmed consumption of liquid sevoflurane at the stage of consumption of sevoflurane, etc.

[0085]

In the “2nd embodiment”, since the container for storing sevoflurane is left at a temperature equivalent to (or below) the temperature at the “stage of sevoflurane consumption (selection stage)”, the liquid phase of sevoflurane is stably present in the container (i.e. equilibrium is established between the liquid and ferry). Therefore, it is possible to maintain a state in which the inner wall of the container is in contact with the “saturated vapor” of sevoflurane.

[0086]

(3) 3rd embodiment

As another technique for stage A (3rd embodiment), the method of blowing all sevoflurane vapor remaining in the storage container for some reason after the consumption stage of the previous batch and then further feeding the sevoflurane outside the container can also be used. ” However, in practice it is unprofitable to first flush the container to remove sevoflurane, and then additionally deliver sevoflurane to the container. As mentioned above, a large amount of sevoflurane is necessary in order to ensure the presence in the storage container of a large capacity of a predetermined volume of sevoflurane vapor in the gas phase. This can lead to wasteful use of sevoflurane. For this reason, the technique for the “3rd Embodiment” is not the best technique in the present invention.

[0087]

A person skilled in the art can appropriately determine whether to perform the “1st Embodiment” or the “2nd Embodiment”. In the case of the “2nd embodiment”, although for this it is necessary to ensure the presence of excess sevoflurane in the storage container, it is possible to ensure a stable presence in the container of saturated sevoflurane vapor. Meanwhile, in the case of the “1st Embodiment,” since essentially all liquid sevoflurane is selected, the vapor pressure of sevoflurane in a container is usually lower (or slightly lower) than the saturated vapor pressure.

[0088]

However, as mentioned above, the authors of the present invention have found that it is certainly possible to provide an affinity for sevoflurane for the inner wall of the storage container even in the case of the “1st embodiment”. Taking into account the maximum prevention of wasteful use of sevoflurane, the “1st variant of implementation” looks more preferable.

[0089]

When stage A is performed using any of the methods for embodiments 1 through 3, it is preferable to create a state in which the sevoflurane vapors are present in the gas phase in the container at stage A, and maintain this state for at least 60 mines in order to allow the inner wall of the container to have an affinity for pairs of sevoflurane. It is even more preferable to maintain this state for 24 hours (day). As can be easily understood from the above explanation, when the “stage of sevoflurane consumption” is completed and the container is hermetically sealed, “stage A” is usually completed in the present invention. The used container for storing sevoflurane in this state is returned (transported) to the manufacturer. Therefore, in most cases, after the stage of sevoflurane consumption, the requirement “to create such a state in which sevoflurane vapors are present in the gas phase in a container for storing sevoflurane, and then maintaining such a state for 1 hour (preferably 24 hours)” is satisfied without performing a special operation, if the container is hermetically sealed after the stage of consumption of sevoflurane.

[0090]

[Concerning Stage B]

At stage B, after completion of stage A, the “liquid containing water as the main component” comes into contact with the inner wall of the storage container for sevoflurane, while the sevoflurane vapors are present in the storage container, and then this liquid is drained from the storage container. storage. As a result of stage B, the sevoflurane remaining in the storage container is washed out of the storage container using liquid. In case sevoflurane contains “polyester 1 and polyester 2”, these analogues can be safely drained together with sevoflurane from the storage container. It is unexpectedly profitable.

[0091]

In the present invention, it is preferable to perform stage A so as to create in advance a state in which sevoflurane vapors are present in the storage container, and then stage B, maintaining such a state (in other words, while the inner wall is in contact with the vapors sevoflurana). Due to this, it is possible to achieve significant washing efficiency in step B of the present invention. Usually a special operation to perform stage B is not necessary. It is only necessary to provide a small opening (inlet) in the storage container for introducing the “liquid containing water as the main component” after stage A, to provide various means of depressurizing, and immediately start to inject the liquid. Accordingly, it becomes possible to replace the “state in which the sevoflurane vapors are in contact with the inner wall” achieved in stage A, “the state in which the liquid containing water as the main component is in contact with the inner wall” in stage B is continuous in a way.

[0092]

When the “liquid containing water as the main component” comes into contact with the inner wall of the storage container of sevoflurane, while the sevoflurane vapor is present in the storage container at stage B of the present invention, this means that the sevoflurane vapor remains in the storage container at the beginning of the contacting of the liquid with the inner wall of the storage container. It is also preferred that the sevoflurane vapors are present in the container and thereafter while the washing with the liquid continues. In particular, in the case of the “2nd embodiment” described below, the amount of fluid used can be reduced, which leads to a decrease in the drainage rate of sevoflurane from the system. Accordingly, sevoflurane vapors tend to remain in the container, while the liquid contacts the inner wall, which is preferred.

[0093]

If liquid sevoflurane remains in the storage container when the above-mentioned stage A is completed (that is, in the case of stage A in the 2nd embodiment described above), liquid sevoflurane can be drained from the fluid drain hole (drain pipe) in the bottom of the storage container before the start of stage B. In particular, when the amount of remaining liquid sevoflurane is large, stage B begins after the liquid sevoflurane is drained, which is preferable because the wasteful use of se Voflurane can be prevented.

[0094]

It is usually difficult to “introduce a liquid containing water as the main component” in stage B while at the same time keeping the storage container completely sealed (due to an increase in internal pressure). Therefore, it is preferable to use pressure release means in the storage container.

[0095]

As indicated above, in accordance with the present invention, a “liquid containing water as a main component” should be a “single-layer liquid containing 50% by weight or more water” and preferably a “liquid essentially consisting of water”. As mentioned above, the main feature of the present invention is that the container for storing sevoflurane can be effectively washed even with the use of a “liquid essentially consisting of water”. This feature avoids the difficulty of managing residual "non-aqueous solvent" in the container.

[0096]

The expression "liquid essentially consisting of water" refers to a liquid consisting of a substance containing, for example, water molecules, which constitute 99.9% by weight of this substance. As mentioned above, it is particularly preferable to use ion-exchanged water or distilled water. With the use of such water, the requirement that "the liquid consists of a substance containing water molecules that make up 99.9% by weight of this substance" is satisfied to a sufficient degree.

[0097]

The temperature of the "liquid containing water as the main component" used in stage B is not particularly limited. It is especially preferable to use a liquid with a temperature of from 60 ° C to 90 ° C for warm or hot water. If the temperature is excessively low, sufficient flushing effects cannot be obtained, which may lead to an increase in the amount of liquid required for flushing. In the meantime, if the temperature exceeds 90 ° C, it becomes difficult to work with a liquid at such an excessively high temperature.

[0098]

In stage B, it is desirable that the “liquid containing water as the main component” be in contact with the entire inner wall of the container for storing sevoflurane in order to remove the chemicals remaining on the inner wall of the container with sufficient washing. The technique for this purpose is not limited; however, representative techniques are described below in the 1st embodiment and the 2nd embodiment.

[0099]

(1) 1st Embodiment

Stage B of the “1st Embodiment” is consistent with the method of filling the storage container completely with “liquid containing water as the main component”, if it is preferred, mixing the liquid for a predetermined period of time and draining the liquid through the drain pipe. This technique does not require a complicated operation and allows the “liquid containing water as the main component” to reliably contact the entire inner wall of the storage container. Thus, in this embodiment, sufficient washing can be performed by a convenient operation. The method of filling the storage container completely with a “liquid containing water as the main component”, mixing the liquid for a predetermined period of time and draining the liquid repeats preferably at least 3 times and more preferably at least 5 times.

[0100]

This technique requires filling the storage container completely with “liquid containing water as the main component”. In this case, the outlet is usually provided at the top of the storage container.

[0101]

The “1st embodiment” is advantageous in that the washing can be performed by a convenient operation. In the meantime, it is disadvantageous in that the amount of “liquid containing water as the main component” has to be adjusted to the internal volume of the storage container in order to perform step B once. In particular, in order to wash, for example, the container for storing large containers with a volume of 500 dm ³ , a large amount of “liquid containing water as the main component” is needed, which can be economically disadvantageous.

[0102]

(2) 2nd embodiment

Stage B of the “2nd Embodiment” corresponds to the method of direct injection of a “liquid containing water as the main component” onto the entire inner wall of the storage container using the liquid injection means. Examples of fluid injection means include conventional means such as a spray nozzle or a shower. Although this technique requires some operation, it is an excellent technique, because sufficient washing can be performed despite the fact that the amount of water used is significantly less than in the 1st embodiment. In addition, as indicated above, since it is possible to reduce the amount of water used in this embodiment, sevoflurane vapors tend to remain in the gas phase for a long time. Even if “polyester 1 and polyester 2” are present, these substances can be removed by vigorous washing, which is advantageous.

[0103]

In the “2nd embodiment”, it is particularly preferable to perform the operation of injecting liquid from the spray nozzle in order to allow liquid droplets ejected from the nozzle to directly collide with the inner wall of the container while gradually changing the angle of the nozzle until the droplets collide with the whole the inner wall of the container.

[0104]

When “water” is used as a solvent, it tends to form a mass with strong intermolecular hydrogen bonds. When the nozzle injects “liquid containing water as the main component” to a specific place alone (for example, in the upper part inside a storage container), droplets of liquid falling inside the container form a line in a specific place and cannot come in contact with the entire the inner wall of the container. This can be prevented by letting the nozzle inject liquid in such a way that the liquid droplets directly collide with the entire inner wall of the container. Accordingly, it is possible that the “liquid containing water as the main component” contacts the entire inner wall of the storage container.

[0105]

The method of injection of the washing liquid is not particularly limited. A wide range of manual or automatic methods can be used. However, as mentioned above, it is common to use a container made of an opaque substance, such as stainless steel, as a container for storing sevoflurane. In such a case, it is usually difficult to “inject water onto the entire inner surface of the container while visually observing the inner part of the container”.

[0106]

In view of the above, it is particularly preferable to carry out stage B in the “2nd embodiment” using the “horizontally rotating spray nozzle”, as shown in FIG. 2. FIG. 2-1 is a sectional view of a container for storing sevoflurane, when viewed in a horizontal direction. FIG. 2-2 is a sectional view of the same container for storing sevoflurane, as seen from above.

[0107]

The “horizontally rotating spray nozzle <a>” is placed near the center of the inside of the storage container (for example, in a central position when viewed in a horizontal direction or in a vertical direction). The nozzle <a> is connected to an external tank, from which “liquid containing water as the main component” is fed to the nozzle <a>. The nozzle <a> injects the supplied water in the direction "obliquely up and to the right at an angle of 90 ° relative to the nozzle <a>" and at the same time in the direction of "obliquely down and to the left at an angle of 90 ° relative to the nozzle <a>". As a result of water injection in the direction “obliquely up and to the right at an angle of 90 ° relative to the nozzle <a>”, the water flow forms a “flat area 1”. As a result of water injection in the direction “obliquely down and to the left at an angle of 90 ° relative to the nozzle <a>”, the water flow forms a “flat area 2”. “Flat area 1” and “flat area 2” are connected through a nozzle <a>, and they are on a plane (one plane) perpendicular to a straight line that connects the observer and the nozzle <a> in FIG. 2

[0108]

FIG. 2 <b> denotes a drainage orifice (or drainage pipe) for draining a liquid, which also serves to relieve pressure in the “2nd embodiment”. Therefore, the drain hole <b> must be open during fluid injection.

[0109]

FIG. 2-1 <c> and <d> respectively denote the upper end and the lower end of the curve, which is formed when “flat region 1” intersects with the inner wall of the container. The lower end of the <c> overlaps the upper center point of the storage container. Meanwhile, <e> and <f> respectively denote the upper end and the lower end of the curve, which is formed when the “flat region 2” intersects with the inner wall of the container. The upper end of the <e> overlaps the lower center point of the storage container.

[0110]

FIG. 2-1 shows that the flushing fluid injected from the nozzle <a> passes through the "flat area 1" and the "flat area 2" and directly faces the curve passing from <c> to <d> and the curve passing from <e> to <f>.

[0111]

Then, the nozzle <a> rotates 360 ° in the horizontal direction with a constant rotation speed, and at this time a state is maintained in which water is injected in the direction "obliquely up and to the right at an angle of 90 ° relative to the nozzle <a>" and in the direction "obliquely down and to the left at an angle of 90 ° relative to the nozzle <a> ", as shown in FIG. 2-1. As a result, the curve that corresponds to the curve extending from <c> to <d> and the curve that corresponds to the curve passing from <e> to <f> is continuously formed in the direction along the inner wall in the 360-degree storage container. In particular, as a result, the sprayed “liquid containing water as the main component” directly collides with the entire inner wall of the container. Accordingly, the inside of the container can be sufficiently washed using a “liquid containing water as the main component” in an amount significantly smaller than that used in the “1st embodiment”.

[0112]

It is preferable that the pressure of the water injected from the nozzle <a> always exceeds the usual pressure, because it is necessary to ensure that the “liquid” is directly confronted with the entire inner wall of the container. For a large container with a volume of 500 dm ^3, this pressure is preferably from 0.2 to 1 MPa (absolute pressure). The speed of the horizontal rotation of the nozzle <a> is not particularly limited; however, in one preferred embodiment, one revolution is performed during a cycle from 0.1 s to 10 s. It should be noted that the speed of rotation of the nozzle <a> is not necessarily critical. As long as the “liquid” is sprayed across the entire inner wall of the container, the rotation speed is not particularly limited (the rotation of the nozzle <a> creates the driving force of the “liquid injection pressure”).

[0113]

A nozzle <a> having the aforementioned fluid injection function is not particularly limited. However, it is preferable to use a commercially available nozzle, such as "CERJET (registered trademark) (manufactured by H. Ikeuchi & Co., Ltd.)." FIG. 3 schematically shows such a nozzle <a>. As shown in FIG. 3, a slit is formed on those nozzle surfaces that are opposite to each other. Feed water is injected through every crevice. Water is injected to form a “flat area 1” from one slot, as well as a “flat area 2” from another slot (the nozzle <a> rotates horizontally to create a driving force “fluid injection pressure” in the example illustrated in Fig. 3). Water is supplied from an external tank. The position, length and width of each slit are determined so that the liquid is injected in the desired directions. When the nozzle <a> is used, having the structure shown in FIG. 3, the slit width is preferably from 0.4 mm to 1 mm (and particularly preferably from 0.5 mm to 0.7 mm).

[0114]

In addition, immediately after the spray nozzle is prepared, a transparent substance, such as acrylic, is used around the flange so that the inside of the container can be controlled from the outside, or the monitor chamber is provided inside the container. The reason for this is that it is preferable to confirm whether a collision of the liquid with the entire inner wall of the container is ensured using the technique described in the “2nd embodiment”. Accordingly, it becomes possible to fine tune how to inject fluid or how to rotate the nozzle in the most appropriate way. Once the optimal operating conditions are determined, they are approved and reproduced in subsequent operations, thereby allowing for efficient washing without frequent monitoring of the inside of the container.

[0115]

When the “2nd embodiment” is applied, a method for continuous “fluid injection by the fluid injection means” can be performed. At the same time, it is also possible to use a method comprising repeating a liquid injection operation for a predetermined period of time (for example, 15 seconds), waiting for a predetermined period of time (for example, 30 seconds), and restarting the injection after a large part of the liquid present on the inner wall will be drained from the drain pipe. In order to preserve the washing liquid, the latter method is preferred. When the latter method is performed for “injecting a liquid with a fluid injection means” and the liquid is divided, for example, into 10 charges, it is possible to sufficiently flush the container with a capacity of 500 dm ³ using the total amount of water, preferably from 30 dm ³ to 500 dm ³ and particularly preferably from 50 dm ³ to 200 dm ³ .

[0116]

Also, when stage B is performed using a “liquid essentially consisting of water” in the “2nd embodiment”, the amount of liquid required is usually from 30 dm ³ to 500 dm ³ and preferably from 50 dm ³ to 200 dm ³ for 500 dm ³ container. As mentioned above, it is possible to obtain excellent washing effects with a smaller amount of washing liquid by injecting a liquid divided into small amounts, several times instead of injecting the entire amount of liquid at once. Therefore, the "amount of water" in itself is not the critical factor that constitutes the present invention. In particular, how to determine the amount of “liquid essentially consisting of water” and the number of times it is washed depends on the material or shape of the storage container, which means that there are different optimal conditions. A person skilled in the art can optimize the above conditions based on his technical knowledge. In order to accomplish the present invention, it is necessary to confirm and comply with the optimized conditions.

[0117]

One possibility for the confirmation described above is to carefully pour a predetermined volume of methanol (it should be noted that sevoflurane and its analog (polyether) can be easily dissolved in methanol) in a storage container after performing stage B in the “2nd embodiment” in a predetermined way so that methanol contacts with the entire inner wall of the storage container, collect the methanol washing liquid through the drain pipe provided in the bottom of the storage container, after after the predefined time interval expires, and analyze this liquid using gas chromatography. More specifically, assuming that the internal volume of the storage container is 100, the volume of methanol poured is preferably from 0.1 to 0.5 (and particularly preferably from 0.2 to 0.4). After the introduction of methanol, the methanol wash liquid (usually in an amount that is approximately 50% of the amount of methanol introduced) is collected to the maximum extent possible through the drain pipe after the expiration, for example, 1 hour. The collected methanol wash liquid can be analyzed by gas chromatography. The authors of the present invention confirmed that after confirming optimal conditions, if stage B was performed in strict accordance with these conditions, sevoflurane and its analogues (polyester 1 and polyester 2) are not detected at the level of sensitivity limit (1 part per million) at subsequent stages in the result of the collection and analysis of methanol washing liquid.

[0118]

In most cases, it is possible to “drain the washing fluid” through the fluid drain opening (drain pipe) provided at the bottom of the storage container, regardless of whether stage B is performed in “1st embodiment” or in “2nd embodiment ". In the case of the “1st embodiment”, it is necessary to completely close the drainage pipe when injecting “a liquid containing water as the main component”. In this case, the pressure is released through the hole formed on the top of the storage container. At the same time, in the case of the “2nd embodiment”, the drain pipe (corresponding to the designation <b> in FIG. 2-1 in the 2nd embodiment) may be opened during the injection of the washing liquid. In this case, the flushing fluid that has come into contact with the inner wall of the storage container is directly drained from the drain pipe, which also serves as a means of pressure relief. In addition to this, in order to avoid leakage of sevoflurane vapor as much as possible to allow sevoflurane vapor to be present in the storage container for a long time, one possibility is to provide an opening for pressure release at the top of the container for storage and to open this opening for pressure relief when closing the drain pipe during the injection of flushing fluid. The person skilled in the art can select this option according to need.

[0119]

Stage B is the stage of washing the container for storing sevoflurane using the “liquid containing water as the main component” as the washing solvent. However, it is also possible to perform “washing with a liquid containing water as a main component” in combination with “washing with purified sevoflurane serving as a washing liquid (rinsing with sevoflurane)” in accordance with the need for the present invention. As stated above, there is no problem in using “liquid containing water as the main component” (and particularly preferably “liquid essentially consisting of water”) to rinse the storage container itself in stage B. One of the important The findings of the present invention are that “polyester 1 and polyester 2” will not be concentrated in a storage container even after washing is performed many times (for multiple batches). Therefore, it is usually not necessary to combine “rinsing with sevoflurane” and washing with sevoflurane.

[0120]

In the case in which the “rinsing with sevoflurane” is performed at stage B, the order of “rinsing with sevoflurane” at stage B is not particularly limited. However, when rinsing with sevoflurane is performed after rinsing with a “liquid containing water as the main component”, a small amount of liquid sevoflurane remains in the storage container after rinsing. Taking this into account, it is preferable to perform the filling stage (2nd stage) as soon as possible after “rinsing with sevoflurane” (for example, within one month at room temperature).

[0121]

Stage B and the subsequent stage C (introduction of the drying gas) can be performed alternately many times. If these two stages are performed alternately many times, this leads to the complexity of these stages. The authors of the present invention have found that in most cases there is no need to perform both stages many times, because sufficient effects can be obtained with a single sequential execution of stages B and C.

[0122]

[Concerning Stage C]

Stage C is the step of introducing the drying gas into the storage container after stage B and draining the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container. By performing step C, it is possible to smoothly drain from the container, together with the drying gas, a portion of the “liquid containing water as the main component” used in stage B, which adheres to (remains on) the inner wall of the container. This operation allows a portion of the “liquid remaining on the inner wall of the storage container” to evaporate in order to drain it from the container. Some of this liquid remains liquid and is directly drained from the container. In addition, even if a small amount of sevoflurane vapor remains in the gas phase in the container after stage B (it should be noted that sevoflurane vapor is essentially completely drained from the container after stage B in many cases), sevoflurane vapor is drained along with the drying gas flow from container at stage C.

[0123]

Thus, it is possible to restore the storage container for sevoflurane so that it is suitable for filling with sevoflurane from the next batch at stage C.

[0124]

As mentioned above, it is possible to repeatedly perform stages B and C alternately many times. At the same time, in most cases, stage B and C can be performed once. In addition to this, it is obvious that if stage B is performed after stage C, stage C must be performed again after stage B, thereby draining the liquid components remaining on the inner wall of the container from the container.

[0125]

As mentioned above, when sevoflurane is shipped as a product, in many cases a small amount of water is added to sevoflurane as a stabilizer. It should be noted that the amount of “water added as a stabilizer” should be strictly controlled for sevoflurane, which is synthesized and purified for the next batch. Therefore, it is very important to completely drain the “water used to rinse the container for storing sevoflurane” from the storage container at stage C, taking into account the quality assurance of sevoflurane as a medicine.

[0126]

The type of drying gas used in step C is not particularly limited. However, dry air is preferably used. It is also possible to use dry nitrogen or dry argon, which is chemically inactive. However, in the present invention it is sufficient to use inexpensive dry air, because sevoflurane and sevoflurane analogues, which are present in liquid form on the inner wall, are completely drained from the storage container in stage B, which is particularly preferable.

[0127]

The method of obtaining dry air is not particularly limited. However, for example, it is convenient and preferable to compress the air using a compressor so as to convert moisture into a liquid, collect the gas phase and pass the gas phase through a “desiccant containing a drying agent such as zeolite or oxidized aluminum” for additional drying. The degree of dryness of the drying gas is not particularly limited. However, if the degree of dryness of the drying gas is higher, stage C can be completed in a shorter period of time. In most cases, the dew point of the drying gas is preferably -30 ° C or less, and more preferably -40 ° C or less.

[0128]

It is possible to introduce drying gas at ordinary temperatures. However, it is preferable to introduce the heated drying gas in order to save time. For example, the drying gas is introduced with a temperature of preferably from 30 ° C to 150 ° C, and more preferably from 40 ° C to 100 ° C.

[0129]

The method of introducing the drying gas in stage C is not particularly limited. However, since the specific gravity of sevoflurane vapor is greater than 1, it is preferable to introduce drying gas from the upper part of the storage container and drain the drying gas from its lower part in stage C. For example, in the case in which the washing liquid is introduced through the inlet in the upper part storage container in stage B, this inlet can be used as an inlet for the drying gas in stage C. It is also possible to use an opening for drainage of liquid (drain pipe) using th in step B, as an opening for discharging drying gas in step C.

[0130]

The flow rate of the drying gas in stage C is not particularly limited. However, this flow rate is preferably from 100 dm ³ / min to 200 dm ³ / min and more preferably from 150 dm ³ / min to 200 dm ³ / min in a container with a capacity of 500 dm ³ .

[0131]

Time of administration may vary depending on conditions. However, the injection time is usually 60 to 300 minutes, when a “liquid consisting essentially of water” is used in stage B, and hot air with a temperature of 30 ° C to 150 ° C is introduced in stage C.

[0132]

As with stage B, the optimum conditions for stage C vary with the material or shape of the container. It is desirable that the person skilled in the art optimizes and confirms these conditions based on his technical knowledge. Once the optimal conditions have been established, it is possible to smoothly carry out stage C in accordance with the established conditions.

[0133]

Stage C may contain a determination of the dew point of the drying gas leaving the storage container after the above steps, and confirming whether the dew point is at or below a predetermined temperature (for example, -20 ° C using a drying gas having a dew point of -30 ° C or less, or -30 ° C when using a drying gas having a dew point of -40 ° C or less). In this case, it is possible to directly determine the dew point of the drying gas leaving the storage container, while simultaneously introducing the drying gas. In addition, it is preferable to temporarily suspend the continuous introduction of the drying gas, seal the container tightly, inject the dry compressed gas into the container, keep the container sealed for a predetermined period of time, and then remove the drying gas, determining the dew point of the drying gas to be removed. In the latter case, it can be confirmed with certainty that there is no moisture deep inside the inner wall. Even after confirming the conditions for stage C, it is preferable to determine the dew point after completion of stage C for all downloads. The reason for this is that stage C is the stage immediately preceding the “2nd stage” of filling the container with sevoflurane from the new lot.

[0134]

FIG. 4 shows one preferred embodiment of stage C.

[0135]

[Especially preferred embodiment of stage 1]

It is possible to perform the 1st stage of the present invention in a particularly preferred manner using a method comprising a combination of the steps a to c described below. In particular, this method is a method for washing the storage container for sevoflurane, in which the storage container is a storage container for sevoflurane, which is reused for multiple batches and undergoes at least a portion of sevoflurane consumption from the previous batch, placed in a storage container , moreover, this method contains the steps:

creating a state in which at least the sevoflurane vapor is present in the storage container by sealingly closing the storage container, while allowing at least part of the sevoflurane vapor to remain in the gas phase in the storage container after sevoflurane consumption at the sevoflurane consumption stage, placed to the storage container from the previous batch (stage a);

direct spraying a liquid essentially consisting of water onto the inner wall of the storage container using a spray nozzle in order to ensure contact of this liquid with the inner wall in a state in which sevoflurane vapors are present in the storage container after stage a, and then draining the liquid from the storage container while the liquid remains liquid (stage b); and

injecting drying gas into the storage container in order to drain the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after step b, and also confirming that the dew point of the drying gas leaving the storage container is equal to or lower than the predetermined temperature (stage c).

[0136]

As a result of stages a – c, sevoflurane and its analogues (polyester 1 and polyester 2) become essentially undetectable in a storage container.

[0137]

In addition, in this embodiment, it is particularly preferable that part or all of the inner wall of the storage container is made of stainless steel, and the temperature of the “liquid consisting essentially of water” is from 60 ° C to 90 ° C.

[0138]

In accordance with the present invention, "a state in which sevoflurane and its analogues (polyester 1 and polyester 2 are not substantially detectable in a storage container" means the following. When the sevoflurane storage container washed with the washing method of the present invention is filled with new sevoflurane (2nd stage) in order to prepare the pharmaceutical product, polyester 1 and polyester 2 from the storage container are essentially not contained in this product . In addition, the content of polyester 1 and polyester 2 does not substantially increase after repeated use of the container for storing sevoflurane for multiple batches. Accordingly, product characteristics of sevoflurane can be provided in a sustainable manner.

[0139]

More specifically, the above condition means that when the content of polyester 1 and polyester 2 in sevoflurane immediately before filling the storage container with sevoflurane from the new batch is defined as α1 (parts per million) and α2 (parts per million), and the content of polyester 1 and polyester 2 in sevoflurane, immediately after filling the storage container, sevoflurane is defined as β1 (parts per million) and β2 (parts per million), both values (β1-α1) and (β2-α2) are less than 1 part per million. Typically, α1 (parts per million) and α2 (parts per million) often become “less than 1 part per million” during the production of sevoflurane. In this case, β1 (parts per million) and β2 (parts per million) become “less than 1 part per million”.

However, another possibility for conveniently confirming whether polyester 1 and polyester 2 are removed is to rinse the inside of the storage container with a predetermined volume of organic solvent (for example, the ratio of the internal volume of the container: the volume of organic solvent = 100: from 0, 1 to 0.5), capable of dissolving sevoflurane (for example, methanol or diethyl ether), and determine whether polyester 1 and polyester 2 are found in the washing liquid at a sensitivity limit of 1 part per million for chromium gas cartography (FID). Past experience shows that if polyester 1 and polyester 2 are not detected in the manner described above, we can assume that the washing operation was successful (see Examples below).

[0140]

Another possibility is to extract the washing liquid collected in each washing operation in step B or b with a predetermined volume of diethyl ether in order to quantitatively determine polyester 1 and polyester 2, as explained in the Examples below. In this case, it is possible to confirm the “flushing effects of each washing operation” (see Examples below).

[0141]

[2] Relative to Stage 2

Stage 2 is the stage of filling the container for storing sevoflurane with fresh sevoflurane, at which sevoflurane and its analogues (polyester 1 and polyester 2) become essentially undetectable as a result of stage 1. The pharmaceutical product of sevoflurane, placed in a storage container, can be produced by performing the 2nd stage in addition to the 1st stage.

[0142]

Sevoflurane is in the form of a liquid with a boiling point of 58.6 ° C. It can be placed in a container in the same way as any other liquid substance. Preferably, sevoflurane contains water in an amount of from 206 ppm to 1,400 ppm, as disclosed in Patent Document 5, so that the stability of sevoflurane can be further improved.

[0143]

It is preferable to perform the 2nd stage by, for example, pre-replacing the air in the storage container with an inert gas (for example, dry nitrogen) at atmospheric pressure and filling the storage container with a predetermined volume of sevoflurane from the new batch. This operation allows the inert gas present in the container to exit the pressure relief port. Usually, after it is placed in a container, sevoflurane gradually forms vapors in the gas phase, thereby slightly increasing the pressure inside the container, as indicated above.

[0144]

Another possibility is to pre-remove air from the storage container and introduce sevoflurane into it, which also falls within the scope of the present invention.

[0145]

The pharmaceutical product thus obtained may be analyzed by gas chromatography by taking a small amount of sevoflurane from a container (i.e., “product analysis”). After stage 1 (stages A - C or a - c) there are essentially no impurities in the container for storing sevoflurane. After the completion of stage 2, the sevoflurane placed in the container is analyzed again, thereby confirming whether the flushing for each load was completed and providing a quality guarantee.

[0146]

In fact, after washing the container using the “solvent essentially consisting of water” in accordance with the present invention, sevoflurane analogs (polyester 1 and polyester 2) were not reliably detected during the “product analysis” even after the container was used for multiple batches . This demonstrates the effectiveness of the present invention.

[0147]

[3] Relative to Stage 3

The 3rd stage is the stage of continuous storage of the container for storage of sevoflurane filled with sevoflurane, as described for the 2nd stage. By performing the 1st stage, 2nd stage and 3rd stage in this order, the sevoflurane from the new batch can be preferably saved.

[0148]

Since sevoflurane placed in the storage container after the 1st and 2nd stages has high stability, the storage temperature is not particularly limited. However, given the use of sevoflurane as a drug, it is preferable to store sevoflurane at a low temperature, below the boiling point (58.6 ° C). Preferably, sevoflurane is stored at a temperature of from 0 ° C to 35 ° C, and more preferably at a temperature close to room temperature (for example, from 10 ° C to 30 ° C).

EXAMPLES

[0149]

Further, the present invention will be described in more detail with reference to the following Examples. However, the present invention is not limited to this. It should be noted that “liquid essentially consisting of water” (simply called “water” in some cases) was used as a detergent in the following Examples, Comparative Examples and Reference Examples. In particular, this liquid was “ion exchange water having an electrical conductivity of 1 μS / cm or less”.

[0150]

[Example 1]

In Example 1, sevoflurane was processed under more severe conditions than the actual storage conditions of sevoflurane, so that a “polyether” was forcibly formed. In particular, in accordance with the disclosure of Patent Document 5, the water content of sevoflurane was lower than that of sevoflurane, obtained as the final product (6 ppm). In addition, sevoflurane was heated to a temperature of 50 ° C in the presence of aluminum oxide (alumina), which serves as a Lewis acid (that is, a substance that is considered in Patent Document 5 as a catalyzing decomposition of sevoflurane). As a result, part of sevoflurane decomposed to polyester, which led to the formation of “sevoflurane containing polyether” in the system. An attempt was made to wash the resulting "sevoflurane containing polyester" with water.

[0151]

(1-1) Drying Sevoflurane (reduced water content)

Sevoflurane (used as a pharmaceutical product) (100 cm ³ ) was placed in an Erlenmeyer flask and cooled to 10 ° C in a refrigerator. Then the synthetic zeolite was introduced into the Erlenmeyer flask so that the weight ratio of the synthetic zeolite: sevoflurane was 1: 4. Then the Erlenmeyer flask was left in the refrigerator at 10 ° C for 2 hours and 30 minutes to dry sevoflurane (water content reduction). After that, the moisture content in sevoflurane was determined using a Karl-Fisher moisture meter, and it was 6 ppm.

[0152]

(1-2) Decomposition of Sevoflurane (Rigid Testing)

Alumina (50 mg) was placed in a brown bottle with a narrow neck 50 cm ³ . Sevoflurane was added to it, having a moisture content of 6 ppm, prepared in paragraph (1-1) (20 cm ³ , 29.9 g).

[0153]

Then the lid of the brown bottle with a narrow neck was closed, and the bottle was heated in a thermostatic bath at 50 ° C for 64 hours. After heating for 64 hours, the bottle was cooled in the refrigerator (at 10 ° C) for 1 hour.

[0154]

(1-3) Removal of Hydrogen Fluoride

Since sevoflurane, obtained as a result of rigorous testing in paragraph (1-2), contained hydrogen fluoride (HF), washing with water (reverse extraction of HF into the aqueous phase) was performed for ease of processing. In particular, sevoflurane, subjected to rigorous testing, and water (15 cm ³ ) were introduced into a separatory funnel made of tetrafluoroethylene, stirred for 1 minute and left for 1 minute, after which the separation of liquids was performed. Then the aqueous phase was collected, and its pH value was checked using a paper pH indicator.

[0155]

The above operations were repeated 3 times. The results for the first, second and third tests of the pH of the aqueous phase were pH = 1, pH = 4 and pH = 6, respectively. It was decided that hydrogen fluoride was removed from the organic phase as a result of the third wash.

[0156]

At the same time, after the third water wash, the composition of the organic phase, as determined by gas chromatography, was as follows: sevoflurane: approximately 87%; polyester 1: 8.4% (84,000 ppm); and polyester 2: 4.0% (40,000 ppm). In addition, 190 ppm of hexafluoroisopropyl alcohol (HFIP) was detected.

[0157]

Here, although the detailed reaction mechanism for converting sevoflurane to “polyester 1” and “polyester 2” is unknown, this reaction may be a series of reactions involving a Lewis acid, as disclosed in Patent Document 5 (see column 4).

[0158]

Patent Document 5 discloses that HFIP (hexafluoroisopropyl alcohol) is also formed during the decomposition reaction. Incidentally, hexafluoroisopropyl alcohol is a water-soluble substance and is also an “amphiphilic substance” with lipophilicity. Therefore, it is believed that a significant part of hexafluoroisopropyl alcohol could enter the aqueous phase upon repeated washing with water (back extraction) 3 times as described above, which allows only part of hexafluoroisopropyl alcohol to remain in the organic phase and results in the above hexafluoroisopropyl alcohol content (“190 ppm”) ).

[0159]

At the same time, the content of polyester 1 or polyester 2 in the organic phase was more than 100 times higher than the content of hexafluoroisopropyl alcohol. This suggests that polyester 1 and polyester 2 are characterized by very high lipophilicity and very low affinity for water, as described herein (which means that it is not possible to process polyester 1 and polyester 2 by back-extraction with water).

[0160]

(1-4 Washing the container with water)

(a) “Sevoflurane containing polyester 1 and polyester 2” prepared above in paragraph (1-3) was collected (5 cm ³ , approximately 10 g) and placed in an autoclave made of stainless steel (SUS304) (internal volume : 500 cm ³ ). After hermetic closing, the autoclave was shaken for 10 minutes so that the inner wall of the autoclave was completely covered with liquid. The autoclave was then left at room temperature for 24 hours (this operation corresponds to “stage A”). It should be noted that the autoclave used in this document has an inlet for washing liquid and a vent in its upper part and a hole for discharging water in its lower part.

[0161]

(b) The water outlet from the autoclave was opened in order to drain the liquid from the autoclave. Then this hole was kept open for 1 min to drain the fluid.

[0162]

(c) The water outlet hole was closed, and then 12.5 cm ^{3 of} water heated to 80 ° C was added. After this, the storage container was sealed. The autoclave was shaken for 10 minutes so that the added water came in contact with the entire inner wall of the autoclave (“first washing with water”).

[0163]

Then the water outlet from the autoclave was opened to drain the fluid from the autoclave. Then this hole was kept open for 1 min to drain the fluid.

[0164]

As described above, the total amount of the drained liquid was collected, cooled with ice, mixed with 0.5 cm ^{3 of} diethyl ether, and shaken well. Accordingly, the lipophilic component was extracted. Then the solution in diethyl ether (called “the composition of the washing liquid of the first washing with water”) was analyzed using gas chromatography (FID). As a result, the concentrations of “polyester 1” and “polyester 2” obtained from the total peak area, including the peak of diethyl ether, were 65 ppm and 76 ppm, respectively (although the peak of sevoflurane was also detected, it was not quantified because most of the sevoflurane evaporated during washing with water at 80 ° C).

[0165]

(d) The autoclave treated in paragraph (c) above was further subjected to a “second water wash” using 12.5 cm ^{3 of} water (at a temperature of 80 ° C) in the manner described in paragraph (c). After extraction with diethyl ether, the composition was determined using gas chromatography (FID). Accordingly, it was determined that the "composition of the washing liquid of the second washing with water" contains "polyester 1" in an amount of 8 parts per million and "polyester 2" in an amount of 13 parts per million.

[0166]

(e) The autoclave treated in paragraph (d) above was further subjected to a “second water rinse” using 12.5 cm ^{3 of} water (at a temperature of 80 ° C) in the manner described in paragraph (d). After extraction with diethyl ether, the composition was determined using gas chromatography (FID). Accordingly, it was determined that the “composition of the washing liquid of the third water wash” contains “polyester 1” in an amount of 1 part per million and “polyester 2” in an amount of 2 parts per million.

[0167]

After that, the “fourth washing with water (at a temperature of 80 ° C)”, “the fifth washing with water (at a temperature of 80 ° C)” and the “sixth washing with water (at a temperature of 80 ° C)” was carried out in the manner described above. The composition of the washing liquid was determined after each washing. Neither "polyester 1" nor "polyester 2" were detected (that is, their concentration was less than 1 part per million). In other words, it has been found that it is possible to effectively remove “polyester 1 and polyester 2” together with the flow of water from the system by repeatedly performing washing with water, preventing them from sticking to the inner surface of the storage container.

[0168]

(1-5 Washing the container with methanol)

To confirm the 2.5 cm ³ ice-cold methanol was introduced into the autoclave after performing the above paragraph (1-4), and washing was performed as described above. The methanol wash liquid was drained from the drain pipe, and this methanol was analyzed by gas chromatography. Accordingly, none of the "sevoflurane", "polyester 1" and "polyester 2" was detected.

[0169]

Thus, it was confirmed that it is possible to sufficiently flush the container for storing sevoflurane by performing a "water wash" in accordance with paragraph (1-4) without performing a "methanol washing" in accordance with paragraph (1-5).

[0170]

As mentioned above, polyester 1 and polyester 2 were forcibly formed by treating sevoflurane under conditions more severe than the actual conditions, and the resulting “sevoflurane containing polyester 1 and polyester 2” was subjected to water washing in Example 1. As a result, although “polyester 1 and polyester 2” were found in the “wash liquid of the third water wash,” the content of “polyester 1 and polyester 2” decreased as the washing was repeated. After the “fourth washing with water,” “polyester 1 and polyester 2” were not detected. Thus, these results confirm that even if “polyester 1 and polyester 2” are formed, having a low affinity for water, their content can be reduced to a level that is pharmaceutically safe, using “liquid essentially consisting of water”, which was impossible to predict in the past.

[0171]

[Example 2]

(Stage A)

The predetermined volume (500 dm ³ ) of sevoflurane product placed in a stainless steel storage container (SUS304) (internal volume: 500 dm ³ ) (i.e., the sevoflurane product from the previous batch placed in a container) was sealed using dry nitrogen and climbed through a siphon tube. When it was found that it was no longer possible to pick up more liquid, the inlet for nitrogen gas and the inlet of the siphon tube were immediately closed.

This led to a state in which sevoflurane vapors were present in the storage container at substantially the pressure of saturated vapor. This condition was maintained at room temperature for one week.

[0172]

(Stage B)

The “horizontally rotating spray nozzle <a>” was attached to a “storage container in which at least a pair of sevoflurane was present” processed in step A, as shown in FIG. 2, followed by water injection. The width of the water injection slot of the spray nozzle <a> (see Fig. 3) was set to approximately 0.6 mm. The hydraulic pressure of the water injected by the spray nozzle was set at 0.4 MPa (absolute pressure), and the flow rate of the water was set at 13.6 dm ³ / min. The spray nozzle <a> rotates horizontally when water pressure is applied. Thus, its rotational speed ranged from 30 to 40 rpm (0.50 to 0.67 rps) under the above conditions. The water temperature (that is, the water temperature in the tank attached to the spray nozzle <a> next to the storage container) was set to 80 ° C.

[0173]

The drain pipe <b> provided at the bottom of the storage container was kept open from the beginning of stage B so that water was injected and water was released through it. First, water was injected for 3 minutes, and then a pause of 60 seconds was made. Then the operation “washing for 15 seconds and a pause for 30 seconds” was repeated 10 times. As a result of this operation, water was injected for a total of 330 seconds. The total volume of water injected over these 330 s was 75 dm ³ .

[0174]

(Stage C)

After stage B, the storage container was subjected to stage C in the embodiment shown in FIG. 3. In particular, stage C was carried out in such a way that the drying gas was introduced from the upper part and exhausted from the drainage pipe provided in the lower part.

[0175]

The drying gas used in this document was “dry air having a dew point of -40 ° C or less (from -40 ° C to -50 ° C)”. This drying gas was heated using a heater so that the temperature of the drying gas (immediately before it was introduced into the storage container) ranged from 60 ° C to 80 ° C. The flow rate of the injected drying gas was set to 170 dm ³ / min. The drying gas was continuously introduced / discharged from the storage container for 2 hours and 40 minutes.

[0176]

After 2 hours and 40 minutes had elapsed, the introduction of the drying gas was stopped, and the inlet and drainage pipe were closed. Then dry air was introduced in order to increase the pressure in the storage container to 0.07 MPa. When the compressed gas inside the container was released (blown out), its dew point was measured, and it was found that it was -30 ° C, which confirms that the water used as the washing liquid was completely removed.

[0177]

(Refilling and analysis)

After the dew point measurement was completed, the storage container was filled with sevoflurane from the new lot. Sevoflurane was collected from the storage container after filling and analyzed. It was found that the collected sevoflurane meets all test standards.

[0178]

[Example 3]

The operations of the experiment described in Example 2, with the exception of the operation described in the section “Refilling and analysis”, were repeated using the same devices (container for storage of sevoflurane with a capacity of 500 dm ³ (made of stainless steel SUS304), a rotating spray nozzle etc.).

[0179]

After completion of the operations corresponding to stages A - C, the container was cooled to room temperature. The lid of the container was then opened, and 1.5 dm ^{3 of} methanol (at room temperature) were directly applied to the entire inner wall of the container instead of performing the operation described in the “Re-filling and analysis” section in Example 2. Thereafter, the methanol wash liquid, which drained from the drainage pipe, was collected and analyzed.

[0180]

As a result, the concentrations of “polyester 1 and polyester 2” were below the sensitivity limit (1 part per million). Thus, when additional washing with methanol was carried out for confirmation after the operations corresponding to stages A – C, “polyester 1 and polyester 2” were not detected. Thus, the effectiveness of washing in stages A - C has been proven with certainty.

[0181]

[Example 4]

After completion of the washing operations (stages A - C) in Example 2, the container for storing sevoflurane was filled with sevoflurane (500 dm ³ ) from the new batch. Then, after completion of the sevoflurane consumption (intake) stage, the storage container was subjected to stages A – C using the means used in Example 2. A number of these operations were repeated using the same container for 20 batches.

[0182]

During the repetition of the aforementioned operations, when the storage container was filled with sevoflurane from the new batch after the washing stage was completed, “polyester 1 and polyester 2” were never found as analogues in the analysis of the product after filling. It was found that all quality standards of sevofluran were satisfied. Thus, it has been demonstrated that the quality assurance of sevoflurane can be reliably achieved using the washing method of the present invention.

[0183]

[Reference Example 1]

A 1 dm ³ autoclave (made of SUS304 stainless steel) used as a storage container for sevoflurane was filled with dry nitrogen. Liquid sevoflurane (i.e., a product of sevoflurane containing 400 parts per million of water) (30 g) was added to it. The autoclave was sealed and stored at room temperature for 1 month. then the moisture content was measured using a Karl-Fischer moisture meter. It was found that the moisture content is 360 ppm. Liquid sevoflurane was stored for one more month in an autoclave in the same manner. Then the moisture content was measured again. It was found that the moisture content is 350 parts per million.

[0184]

As described above, when a small amount of sevoflurane is stored with a large amount of drying gas in a large-capacity storage container, the moisture content in the liquid phase may decrease over time, although the reason for this is unclear. In fact, the water content is usually reduced slightly, as in the case of Example 1. However, if a small amount of sevoflurane remains at the bottom of the storage container after the consumption stage of the sevoflurane is consumed, such sevoflurane may behave differently from the usual “sevoflurane” placed in the storage container. Taking this into account, the data obtained above suggest that it is absolutely necessary to wash the storage container thoroughly in order to reliably achieve quality assurance of sevoflurane.

[0185]

[Reference Example 2]

"Sevoflurane containing polyester 1 and polyester 2" was prepared in accordance with the procedures and amounts described in paragraphs (1-1) - (1-3) of "Example 1". Then "rinsing with sevoflurane" was carried out instead of paragraph (1-4).

[0186]

In particular, the procedures (a) and (b) in paragraph (1-4) of Example 1 were performed as in Example 1. Then the washing was performed 3 times using 12.5 cm ³ “product of sevoflurane” (at room temperature) instead of using 12.5 cm ^{3 of} water in the procedure (c) of paragraph (1-4) of Example 1. The resulting washing fluid of sevoflurane was drained from the drainage tube and analyzed by gas chromatography. As a result, the concentrations of "polyester 1" and "polyester 2" in sevoflurane drained from the drain pipe were 4 ppm and 5 ppm, respectively, for the first measurement. The concentration of "polyester 2" in sevoflurane, drained for the second dimension, was 1 part per million, while no "polyester 1" was detected. Neither "polyester 1" nor "polyester 2" was detected in sevoflurane drained for the third dimension.

[0187]

As mentioned above, it was confirmed that “polyester 1 and polyester 2” can be sufficiently washed using expensive sevoflurane as a washing liquid due to the lipophilicity of sevoflurane.

[0188]

[Reference Example 3]

The procedures of Example 1 were performed in the same way, except that the procedures (a) and (b) in paragraph (1-4) were modified as described below.

[0189]

In particular, “sevoflurane containing polyether” was introduced into a 500 dm autoclave.³, and good contact with the inner wall of the autoclave was ensured. Then the water outlet from the autoclave was immediately opened in order to drain the liquid from it without performing the “autoclave aging for 24 hours” procedure (a) in paragraph (1-4) (stage A). After that, the lid of the autoclave was left open and the autoclave was left at room temperature for 3 days. Accordingly, the sevoflurane in the sample evaporated, and therefore the inner wall of the container dried out.

[0190]

Thereafter, the first washing with water was performed in the manner described above, followed by ice-cooling and extraction with diethyl ether. As a result, the concentrations of “polyester 1” and “polyester 2” were 7 ppm and 12 ppm, respectively. As a result of the second water wash, the concentrations of “polyester 1” and “polyester 2” were 5 ppm and 9 ppm, respectively. As a result of the third water wash, the concentrations of “polyester 1” and “polyester 2” were 3 parts per million and 7 parts per million, respectively.

[0191]

When the inside of the storage container was dried without performing step A, as described above, it sometimes became difficult to remove the polyester even by washing with water.

[0192]

[Comparative Example 1]

"Sevoflurane containing polyester 1 and polyester 2" was prepared in accordance with the procedures and amounts described in paragraphs (1-1) - (1-3) of "Example 1". Then "sevoflurane containing polyester 1 and polyester 2" was provided a good contact with the inner wall of the container by an operation corresponding to paragraph (1-4) of "Example 1". Then, “rinsing the container with acetone” was performed instead of “rinsing with water”.

[0193]

In particular, the procedures (a) and (b) in paragraph (1-4) of Example 1 were performed as in Example 1. Then the washing was performed 3 times using 12.5 cm ^{3 of} acetone (at room temperature) instead of using 12 , 5 cm ^{3 of} water in the procedure (c) of paragraph (1-4) of Example 1. The resulting acetone washing fluid was drained from the drain pipe and analyzed by gas chromatography. As a result, the concentrations of "polyester 1" and "polyester 2" in acetone drained from the drain pipe were 3 parts per million and 2 parts per million, respectively, for the second dimension. Neither "polyester 1" nor "polyester 2" was detected in drained acetone in the third dimension.

[0194]

Thereafter, dry air with a temperature of 60 ° C to 80 ° C was allowed to circulate in the storage container for 60 minutes. Then 3 cm ³ of sevoflurane product was reintroduced into the storage container and contacted with the inner surface of the storage container. This sevoflurane was analyzed by gas chromatography.

[0195]

As a result, a peak of a small amount of acetone was detected, while “polyester 1 and polyester 2” were not detected.

[0196]

When acetone was used as a washing liquid, as described above, it was surprisingly difficult to remove acetone, although it was possible to remove “polyester 1 and polyester 2”. This suggests that rinsing with acetone may not always be an effective rinse.

INDUSTRIAL APPLICABILITY

[0197]

In accordance with the present invention, it is possible to effectively wash the used “container for storage of sevoflurane” with an inexpensive liquid containing water as the main component. In particular, washing can be performed to such an extent that essentially neither sevoflurane nor its analogues (polyester 1 and polyester 2) can be found in the storage container.

In addition, in accordance with the present invention, it is possible to separately perform the washing step of the storage container and the subsequent filling step of the storage container with sevoflurane, thereby allowing an increase in the degree of freedom for each stage.

Claims (32)

1. A method for washing a storage container for sevoflurane, where the storage container is a storage container for sevoflurane, which is reused for multiple batches and that has been subjected to at least a portion of sevoflurane from a previous batch, placed in a storage container, moreover, this method includes the steps: creating a state in which at least a pair of sevoflurane is present in the storage container (stage A); bringing into contact of a liquid consisting of a substance containing water molecules, which constitute 99.9 wt.% or more of this substance, with the inner wall of the container for storing sevoflurane in a state in which vapors of sevoflurane are present in the storage container after stage A , and draining the liquid containing sevoflurane from the storage container as long as it remains liquid (stage B); and the introduction of the drying gas in the storage container in order to remove the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after stage B (stage C), where, as a result of the implementation of stages A – C, sevoflurane and its analogues (polyester 1 and polyester 2) described by the following formulas are present in a storage container in an amount of less than 1 ppm: (CF ₃ ) ₂ CHO-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 1> (CF ₃ ) ₂ CHO-CH ₂ -O-CH ₂ -O-CH (CF ₃ ) ₂ <Polyether 2>. 2. The washing method of claim 1, wherein the state in which at least the sevoflurane vapors are present in the storage container in step A is the state that results from using essentially all of the liquid sevoflurane from the storage container in step consuming sevoflurane placed in a storage container from the previous batch, and then sealing the storage container tightly, allowing at least part of the sevoflurane vapor to remain in the gas phase in the storage container. 3. The washing method of claim 1, wherein the state in which at least the sevoflurane vapors are present in the storage container in step A is a state that is formed when using part of the liquid sevoflurane from the storage container in the sevoflurane consumption stage placed in storage container from the previous batch, and then sealing the storage container tightly. 4. Method of washing according to any one of paragraphs. 1-3, in which to bring into contact a liquid consisting of a substance containing water molecules, which constitute 99.9 wt.% Or more of this substance, with the inner wall of the storage container of sevoflurane in stage B, the liquid is injected directly onto the inner wall storage container using liquid injection. 5. The washing method according to claim 4, wherein the temperature of the liquid consisting of a substance containing water molecules, which constitute 99.9 wt.% Or more of this substance, is 60 to 90 ° C when injected. 6. Method of washing according to any one of paragraphs. 1-5, in which part or all of the inner wall of the storage container is made of at least one material selected from the group consisting of stainless steel, a polymer coating and glass. 7. The washing method according to claim 6, wherein part or all of the inner wall of the storage container is made of stainless steel. 8. Method of washing according to any one of paragraphs. 1-7, in which the drying gas in stage C is dry air with a temperature of from 30 to 150 ° C. 9. Method of washing according to any one of paragraphs. 1-8, in which step C includes confirming that the drying gas leaving the storage container has a dew point equal to or less than a predetermined temperature of -20 ° C using a drying gas having a dew point of -30 ° C or less, or -30 ° C when using a drying gas having a dew point of -40 ° C or less. 10. A method for washing the container for storage of sevoflouran, where the storage container is a storage container for sevoflurane, which is reused for multiple batches and that has been subjected to consumption stages for at least part of sevoflurane from the previous batch, placed in a storage container moreover, this method includes the steps: creating a state in which at least the sevoflurane vapor is present in the storage container as a result of the tight closing of the storage container, while allowing at least part of the sevoflurane vapor to remain in the gas phase in the storage container after using sevoflurane at the sevoflurane consumption stage, placed in a storage container from the previous batch (stage a); direct spraying of a liquid consisting of a substance containing water molecules, which is 99.9 wt.% or more of this substance, onto the inner wall of the storage container using a spray nozzle in order to bring the liquid into contact with the inner wall in a state wherein the sevoflurane vapors are present in the storage container after stage a, and then draining the liquid containing sevoflurane from the storage container while the liquid remains liquid (stage b); and introducing the drying gas into the storage container in order to remove the liquid remaining on the inner wall of the storage container, together with the drying gas from the storage container after step b, and also confirming that the dew point of the drying gas leaving the storage container is equal to or lower than the predefined temperature of -20 ° C when using a drying gas having a dew point of -30 ° C or less, or -30 ° C when using a drying gas having a dew point of -40 ° C or less (stage c ), where, as a result of carrying out steps a - c, sevoflurane and its analogues (polyester 1 and polyester 2) described by the following formulas are present in a storage container in an amount of less than 1 part per million: (CF ₃ ) ₂ CHO-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 1> (CF ₃ ) ₂ CHO-CH ₂ -O-CH ₂ -O-CH (CF ₃ ) ₂ <Polyester 2> 11. The washing method according to claim 10, wherein part or all of the inner wall of the storage container is made of stainless steel, and the temperature of the liquid, essentially consisting of water, is from 60 to 90 ° C. 12. A method of obtaining a pharmaceutical product, which is sevoflurane, placed in a storage container, including washing the storage container according to the method according to any one of claims 1 to 11 and then filling the storage container with new sevoflurane. 13. The production method according to claim 12, wherein the liquid composition of sevoflurane from a new batch, placed in a storage container, is analyzed by gas chromatography. 14. A method for storing sevoflurane, comprising the following steps 1-3: The 1st stage of washing the container for storing sevoflurane by the method according to any one of claims. 1-11; The 2nd stage of filling the storage container with sevoflurane from the new batch after washing the container; and The 3rd stage of storage of a container for storing sevofluran after filling it.

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