JP6837895B2 - Manufacturing method of pharmaceutical solution preparation - Google Patents

Description

The present invention relates to a method for producing a solution preparation using a pharmaceutical active ingredient, which is concerned about the production of related substances due to oxidation. Specifically, it is an efficient method for removing oxygen in a solution for producing a solution preparation using an active ingredient having physical properties that easily generate related substances by oxidation with oxygen, and the oxygen removing method is used. The present invention relates to a method for producing a solution preparation.

Injectable pharmaceutical preparations are generally classified into freeze-dried preparations and solution preparations. Although the lyophilized preparation has excellent storage stability, it requires a dissolution operation at the time of use, and a sufficient mixing operation is required to completely dissolve it. Therefore, in the medical field, there is a demand for a so-called RTU (Ready-to-use) preparation in the form of a solution that does not require a complicated dissolution operation and can be diluted and immediately administered.
However, in the case of a solution-type preparation, many active ingredients undergo a hydrolysis reaction or an oxidation reaction to produce related substances in an aqueous solution. In particular, the decomposition of the active ingredient by the oxidation reaction due to the presence of oxygen in the preparation is often a problem. Therefore, in order to formulate a solution, it is required to remove the dissolved oxygen in the solution and the oxygen in the voids in the preparation container such as a vial as much as possible in order to suppress the oxidation reaction by oxygen.

For example, it is known that pemetrexed disodium, which is known as an antitumor agent, rapidly undergoes an oxidation reaction with oxygen in an aqueous solution to produce a related substance. Therefore, pemetrexed disodium is provided to medical institutions as a lyophilized preparation, and no solution preparation is provided. However, as described above, since there is a demand for simplification of work at the time of administration in medical institutions, research and development of solution-type RTU preparations are also being promoted for pemetrexed disodium preparations that are easily oxidized in a solution.
Regarding pemetrexed disodium solution preparations, there have been reports of preparation formulations using various antioxidants, but in many reported cases, measures have been taken to reduce the oxygen content in the preparations. For example, Patent Document 1 discloses a pemetrexed disodium solution preparation having an oxygen partial pressure of 0.2% or less, which includes decompression degassing, distillation degassing, nitrogen bubbling, membrane degassing, and catalytic resin degassing. It states that it will be used. Further, in Patent Documents 2 and 3, a solution having an oxygen concentration of 0.1 to 2.0% by volume or less is obtained by stirring an aqueous pemetrexed solution at room temperature for 2 hours under a nitrogen atmosphere and then filtering the solution with a 0.2 μm filter. Preparing the formulation. These methods require various operation steps such as distillation in a nitrogen atmosphere, stirring and filtration, and are difficult to apply to an industrial manufacturing method corresponding to scale-up.
According to Patent Document 4, a pemetrexed disodium solution preparation in which the amount of oxygen in the void (head space) in the vial is adjusted to 3 to 5% by volume is prepared by dispensing the drug solution into a vial and then purging with nitrogen. There is. Further, Patent Document 5 discloses a method in which a solution is frozen in a closed chamber using a freeze dryer, depressurized, repressurized with nitrogen, and stoppered, and the dissolved oxygen concentration of the solution is 0. It is stated that it was removed to about 5 ppm.

In order to prepare a solution preparation using an active ingredient that is unstable to oxidation, it is effective to reduce the dissolved oxygen in the solution and the oxygen content in the voids in the sealed unit preparation. Although various methods are known for deaeration, it is also an important requirement to ensure sterility of solution preparations used as injection preparations. Therefore, it can be operated aseptically, and it is possible to mass-produce vials of about 1 to 100 mL in which the dissolved oxygen in the solution is reduced and the oxygen concentration in the void is 0.5 (v / v)% or less, which is industrially compatible. There is a need for a method for producing a possible pharmaceutical solution preparation.

International release WO2012 / 121523 International release WO2015 / 145911 International release WO2015 / 050230 Special Table No. 2016-518404 Special Table No. 2017-506213

An object to be solved by the present invention is to provide a method for highly removing the amount of oxygen in a solution formulation in the production of a pharmaceutical solution formulation without using special manufacturing equipment on an industrial production scale. .. That is, to provide a method for producing a solution preparation using the oxygen removing method.

The present invention discloses a method for producing a pharmaceutical solution preparation, which comprises steps 1 to 7 according to the following (a) to (g), which can highly remove oxygen in the preparation.
[1] A method for producing a sealed pharmaceutical solution preparation having a reduced oxygen content.
(A) Step 1 of preparing a chemical solution containing an active ingredient,
(B) Step 2 of injecting the chemical solution into a sealable container,
(C) Step 3 of lowering the chemical solution to 20 ° C. or lower
(D) Step 4 of reducing the pressure of the chemical solution to a pressure higher than the vapor pressure of the solvent of the chemical solution and lower than the atmospheric pressure.
(E) Step 5 of recovering the atmospheric pressure with an inert gas that does not substantially contain oxygen.
(F) Step 6, in which the chemical solution is allowed to stand in the inert gas atmosphere at a temperature equal to or higher than the freezing point of the chemical solution.
(G) Step 7 of sealing the container containing the chemical solution in an atmosphere of an inert gas that does not substantially contain oxygen.
A method for producing a pharmaceutical solution preparation according to the above.
The present invention is characterized by an operation step that combines a step of preparing an inert gas atmosphere after cooling the chemical solution and a step of exposing the chemical solution to the inert gas atmosphere in a liquid state. In the production method of the present invention, the oxygen content in the unit formulation can be controlled by performing the steps of cooling, depressurization, purging with an inert gas, and tapping using a unit formulation container infused with a chemical solution. it can. These process operations can be performed by using a closed chamber device that is usually installed for preparing a pharmaceutical product, such as a freeze-dryer for producing a normal pharmaceutical product, and contains oxygen without using special equipment. It is possible to prepare a solution formulation with a reduced amount.

[2] The method for producing a pharmaceutical solution preparation according to the above [1], wherein in step 4, the pressure is reduced to 1.01 times or more and 5.0 times or less the atmospheric pressure of the vapor pressure of the chemical solution.
[3] The method for producing a pharmaceutical solution preparation according to the above [1] or [2], wherein in step 6, the product is exposed to the inert gas atmosphere for 5 hours or more.
One of the features of the production method of the present invention is (f) that the chemical solution is allowed to stand in the inert gas atmosphere at a temperature equal to or higher than the freezing point of the chemical solution. A solution preparation having a reduced oxygen content in the unit preparation can be prepared by allowing it to stand in an inert gas atmosphere for a long time at a temperature equal to or higher than the chemical freezing point.

[4] The chemical solution is filled with 50 (v / v)% or more of the volume of the container, and the oxygen concentration in the void of the container is 0.5 (v / v)% or less. The method for producing a pharmaceutical solution preparation according to any one of [3].
[5] The method for producing a pharmaceutical solution preparation according to any one of the above [1] to [4], wherein the active ingredient is pemetrexed disodium, which is an aqueous solution preparation containing water as a main solvent component.
The production method of the present invention can be applied to a solution preparation of a pharmaceutical active ingredient that is susceptible to an oxidation reaction by oxygen. As a desirable specific example, a method for producing an aqueous solution preparation using pemetrexed disodium as the active ingredient can be mentioned.

The method for producing a pharmaceutical solution formulation of the present invention can produce a solution formulation with a highly reduced oxygen content in a unit formulation without using special equipment on an industrial scale. By introducing this manufacturing method into the manufacturing process of solution preparations, even active ingredients whose impurities tend to increase by reacting with oxygen in the solution state can maintain their efficacy and safety for a long period of time. It will be possible to provide.

The present invention is a method for producing a pharmaceutical solution preparation using a step capable of highly removing oxygen in a solution preparation on an industrial scale. The details will be described.
In the method of the present invention, a container filled with a solution is placed in a space that can be sealed, and the inside of the space is depressurized to a degree higher than the vapor pressure at an arbitrary temperature of the chemical solution, and then an inert gas is depressed. It is a method of highly removing dissolved oxygen present in the solution preparation and oxygen in the voids by injecting and sealing the solution.
In the production method of the present invention, a unit preparation container in which a chemical solution is injected is used, and the unit preparation is carried out by the operation steps of (A) cooling, (B) depressurization, (C) decompression by inactive gas purging, and (D) tapping. It is a method of controlling the oxygen content in. The details of the device capable of (A) temperature control, (B) depressurization control, (C) repressure control by an inert gas, and (D) sealing used in the present invention will be described.

(A) Temperature control The temperature control in the present invention is performed to control the vapor pressure of the chemical solution by changing the temperature of the chemical solution containing the active ingredient. The range of temperature control is not limited as long as the vapor pressure can be controlled for the solution filled in the container. As an example, when the solution filled in the container is an aqueous solution, the range of temperature control is preferably -100 ° C to 100 ° C. Further, as a device for controlling the temperature, a device capable of controlling the temperature of the solution by controlling the temperature of the shelf in direct contact with the container is preferable.

(B) Decompression control The decompression control in the present invention is performed in order to reduce the atmospheric pressure in the apparatus to 1.01 times or more and 5.0 times or less the atmospheric pressure of the vapor pressure at the control temperature of the chemical solution. The ability of decompression control is not limited as long as it is possible to reduce the pressure to 5.0 times or less at 1.01 times or more the vapor pressure at the control temperature of the chemical solution filled in the container. As an example, if the chemical solution filled in the container is an aqueous solution, it is preferable that the decompression capacity can be reduced to about 20 Pa. As a device for controlling the depressurization, it is preferable to use a vacuum pump such as an oil rotary vacuum pump or a dry pump. In addition, it is necessary to have a function that can maintain and control an arbitrary degree of decompression. The device is preferably a device provided with a closed chamber capable of maintaining a degree of decompression.

(C) Restoration control using an inert gas The repressure control using an inert gas in the present invention is performed in order to raise the air pressure in the depressurized device with the inert gas. The inert gas is a gas that does not substantially contain oxygen and does not react with active ingredients, preparation additives, preparation components such as solvents, and preparation materials such as vials and rubber stoppers. The inert gas may be any gas as long as it does not cause any problem even if it diffuses into the environment and does not react with the solution components in the container, but it is preferable to use argon or nitrogen. The inert gas is preferably sterilized by a gas sterilization filter or the like. There is no limit to the inflow rate of the inert gas into the device as long as there is no effect such as the container in the device falling over or the half-stopped rubber stopper falling off.

(D) Sealing The sealing in the present invention is performed to seal a container containing a chemical solution recompressed by an inert gas in the device. Any method of sealing may be used as long as oxygen does not flow into the device and the container. Preferably, the container filled with the solution and semi-stopped with a rubber stopper undergoes the steps of (A) cooling, (B) depressurization, and (C) decompression by an inert gas purge, and is placed on the container. This is a method in which a rubber stopper is pushed into a container and sealed by lowering the surface. Half-stopping means that the container is not completely sealed, there is a gap between the mouth of the container and the plug, and gas can enter and exit.

Since the oxygen removing method of the present invention is used in the step of preparing an injectable solution, which is a sterile preparation, it is preferable that the apparatus used in the method of the present invention can be sterilized. As a sterilization method for the device, a sterilization method using high-pressure saturated steam is preferable.
The operations of (A) temperature control, (B) decompression control, (C) repressure control by inert gas, and (D) sealing used in the present invention are the operations of the usual manufacturing process of the pharmaceutical preparation for injection. It is done, and does not require special equipment. For example, the freeze-drying apparatus with a stoppering function used for producing a freeze-dried preparation is an apparatus capable of performing all the operations (A) to (D) in a sterile environment, and the production of the present invention. It is the preferred device for application to the method.

Next, a method for producing a pharmaceutical solution preparation using the oxygen removal method using the apparatus described above will be described. In the method for producing a solution preparation in the present invention, a container filled with a chemical solution is placed in a closed space, and the chemical solution is cooled to an arbitrary temperature of 20 ° C. or lower, preferably 10 ° C. or lower, more preferably 0 ° C. or lower. Then, the pressure is reduced based on the vapor pressure at the arbitrary temperature, and then an inert gas is injected and allowed to stand, and by sealing the container, oxygen in the container is highly removed to manufacture the solution preparation. How to do it.

The present invention requires (a) step 1 of preparing a chemical solution containing an active ingredient as a first step. The active ingredient is not particularly limited as long as it is administered parenterally, but is preferably an active ingredient that is decomposed by an oxidation reaction caused by oxygen. For example, ascorbic acid, ergomethrin, famotidine, chlorpromazine, prochlorperazine, perphenazine, verteporfin, promethasone, levomepromazine, carbazochrome sulfonic acid, amikacin, procaine, bidarabin, albecacin, edrophonium, isepamicin, dopamine, adrena , Gentamicin, enocitabine, sulpyrine, azacetron, dexamethasone, dobutamine, tobramycin, phenylephrine, mitoxanthrone, aprinzine, edarabon, edrophonium, kanamycin, dibecasin, danaparoid, pyridoxal, betamethasone, mesalazine, methoclopramide, ribostamycin, etc. Although it can be mentioned, particularly preferably, it is pemetrexed, and it is preferable to use it in a solution preparation containing pemetrexed disodium as an active ingredient.

The solution formulation used in the present invention is a solution formulation prepared using a solvent. The solvent is not particularly limited as long as it is acceptable as a solvent for parenteral administration. For example, water, ethanol, polysorbate 80, macrogol, glycerin, polyoxyethylene hydrogenated castor oil and the like can be mentioned, and these may be used alone or as a mixed solvent of two or more kinds. The solvent is preferably of a quality that can be administered parenterally. A particularly preferable solvent is a water-containing solvent containing water as a main component. An embodiment in which only water is used as the solvent may be used.

The solution formulation used in the present invention may contain a pharmaceutically acceptable additive. In particular, as long as it can be administered parenterally, it can be used without particular limitation. Additives may include antioxidants, buffers, pH regulators, tonicity agents, chelating agents and stabilizers.
Antioxidants are additives used to suppress the decomposition of active ingredients by oxidation. Examples thereof include ascorbic acid, cysteine, sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite, alpha thioglycerin, citric acid, sodium thioglycolate, sodium edetate, methionine, tocopherol, butylhydroxyanisole, and dibutylhydroxytoluene.
A buffer is an additive used to keep the pH constant. For example, citrates, phosphates, acetates and the like are used.
A pH regulator is an additive used to keep the pH within a set range. For example, hydrochloric acid, sodium hydroxide, acetic acid and its salt, phosphoric acid and its salt, citric acid and its salt, tartaric acid and its salt and the like are used.
An isotonic agent is an additive used to bring the osmotic pressure of serum closer. For example, sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotine amide, glucose, purified sucrose, mannitol, macrogol and the like can be mentioned.
A chelating agent is an additive that indirectly suppresses decomposition due to the presence of metal ions by forming a complex with metal ions. For example, disodium ethylenediaminetetraacetate, citric acid and its salt, tartaric acid and its salt, gluconic acid and its salt and the like can be mentioned.
The stabilizer is used for various purposes such as suppressing the decomposition of the active ingredient and stabilizing the particles. For example, acetyltryptophan, alanine, arginine and its salts, albumin, benzoic acid and its salts, inositol, ethanol, histidine and its salts, fructose, caldiamide sodium, sodium carbazochrome sulfonate, sodium carbonate, xylitol, glycine, glutamate and its salts. Salt, creatinine, sodium dihydrogen phosphate, sodium chondroitin sulfate, diethanolamine, diethylenetriamine pentaacetic acid, cystine, dibutylhydroxytoluene, calcium bromide, purified gelatin, purified soybean lecithin, gelatin, sorbitanoic acid fatty acid ester, sorbitan sesquioleate, Sorbitol, sodium hydrogen carbonate, potassium thiocyanate, dextran, calcium saccharide, triethanolamine, tromethamole, sodium formaldehyde sulfosylate, nicotinic acid amide, lactic acid, lactose, urea, propyl paraoxybenzoate, methyl paraoxybenzoate, glacial acetic acid , Butylhydroxyanisole, propylene glycol, benzalconium, benzyl alcohol, benzethonium, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polysolvate 20, polysolvate 80, macrogol, maltose, sodium pyrophosphate, maleic acid, phosphorus Acids and their salts, meglumine, sodium metasulfobenzoate, monoethanolamine, lysine hydrochloride, magnesium sulfate and the like can be mentioned.
Since the solution preparation according to the present invention is a solution preparation using an active ingredient that is easily oxidized, it preferably contains an antioxidant.

As the pharmaceutical solution preparation of the present invention, an aqueous solution preparation in which the active ingredient is pemetrexed disodium and water is the main solvent component can be mentioned as a preferable embodiment. Further, an aqueous solution preparation in which the active ingredient is pemetrexed disodium and water is used as a solvent component can be mentioned as a preferable embodiment.
In the case of an aqueous solution of pemetrexed disodium, an antioxidant, a pH adjuster, a buffer, an isotonic agent, and a chelating agent may be optionally contained.
Antioxidants include ascorbic acid, cysteine, sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite, alpha thioglycerin, citric acid, sodium thioglycolate, sodium edetate, methionine, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, etc. Can be given.
As the pH adjuster, hydrochloric acid, sodium hydroxide, acetic acid or a salt thereof, phosphoric acid or a salt thereof, citric acid or a salt thereof, tartaric acid or a salt thereof or the like may be used.
As the buffer, citrate, phosphate, acetate or the like may be used.
As the tonicity agent, sodium chloride, calcium chloride, magnesium chloride, glycerin, fructose, xylitol, sorbitol, trehalose, nicotine amide, glucose, purified sucrose, mannitol, macrogol and the like may be used.
As the chelating agent, disodium ethylenediaminetetraacetate, citric acid or a salt thereof, tartaric acid or a salt thereof, gluconic acid or a salt thereof or the like may be used.
In the case of an aqueous solution preparation of pemetrexed disodium, it is preferable that the preparation contains an antioxidant and a pH adjuster.

Next, (b) step 2 of injecting the chemical solution into a sealable container is a requirement.
The sealable container for filling the chemical solution is a container such as a vial that can be sterilized and is a hermetically sealed preparation container that can be sealed with an airtight rubber stopper.
The container to be used is not particularly limited in shape such as a vial or a syringe as long as it can be sealed with a rubber stopper or the like, but a vial shape is preferable. Examples of the material of the container include soda lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer. Further, as the container, a surface-treated container can be used for the purpose of improving stability and suppressing elution.
A highly deoxidized injectable solution preparation can be prepared by deoxidizing the container according to the method of the present invention and sealing it with an airtight rubber stopper. As the material of the rubber stopper, it is preferable to use a rubber stopper made of butyl rubber or a rubber stopper made of butyl rubber laminated with a fluororesin.
These sealable containers are preferably packaging materials that have been sterilized by an appropriate method for both the container and the rubber stopper.

The chemical solution prepared in (a) above is injected into the sealable container. The injection amount may be appropriately set according to the container capacity. It is preferable that the volume of voids not filled with the chemical solution is as small as possible with respect to the container capacity.
Preferably, the drug solution is injected so that 50 (v / v)% or more of the volume of the container is filled. More preferably, the chemical solution is 60 (v / v)% or more of the volume of the container, and 65 (v / v)% or more is filled with the chemical solution.

Next, (c) step 3 of lowering the chemical solution to 20 ° C. or lower is a requirement.
After installing the container filled with the solution in the device, the temperature is controlled. Temperature control is performed to control the vapor pressure of the solution. In general, the lower the temperature, the lower the vapor pressure of the solution. Therefore, by lowering the chemical solution temperature to 20 ° C. or lower, the vapor pressure of the solution is lowered, and the threshold value of the atmospheric pressure at which the solution boils is lowered. It becomes possible to remove more oxygen inside.
For example, in the case of water, when the temperature control inside the device is 20 ° C, the vapor pressure of water at 20 ° C is about 2,330 Pa, so the decompression inside the device can be reduced to about 2,400 Pa. is there. Therefore, in the next step, when the inside of the device is restored to atmospheric pressure (1 atmosphere ≈ 101,300 Pa) with an inert gas, the oxygen concentration in the device is 21 (v) before the pressure is reduced. Assuming / v)%, 21 (v / v)% × 2,400 Pa / 101,300 Pa = about 0.50 (v / v)%. When the temperature control in the device is 10 ° C., the vapor pressure at 10 ° C. is about 1,230 Pa, and the decompression in the device can be reduced to about 1,300 Pa. At that time, when the inside of the device was restored to atmospheric pressure with an inert gas in the next step, the oxygen concentration in the device was 21 (v / v)% × 1,300 Pa / 101,300 Pa = about 0.27 ( It is removed up to v / v)%.
Further, when the temperature control in the device is set to 0 ° C., the vapor pressure of water at 0 ° C. is about 610 Pa, and the decompression in the device can be reduced to about 700 Pa. At that time, when the inside of the device was restored to atmospheric pressure (1 atmosphere ≒ 101,300 Pa) with an inert gas in the next step, the oxygen concentration in the device was 21 (v / v)% × 700 Pa / 101,300 Pa. = Removed up to about 0.15 (v / v)%. Further, when the temperature control in the device is set to −40 ° C., the vapor pressure of water at −40 ° C. is about 20 Pa, and the decompression in the device can be reduced to about 50 Pa. At that time, when the inside of the device was restored to atmospheric pressure (1 atmosphere ≈ 101,300 Pa) with an inert gas in the next step, the oxygen concentration in the device was 21 (v / v)% × 50 Pa / 101, 300 Pa =. It is about 0.01 (v / v)%. Therefore, by controlling the temperature before depressurizing, it is possible to remove oxygen in the apparatus to a higher degree in the next step by lowering the temperature. The temperature control before depressurization is preferably 20 ° C. or lower, and more preferably 10 ° C. Hereinafter, it is more preferably 0 ° C. or lower.
Since the chemical solution is allowed to stand in a solution state in step 6 (f) described later, the temperature may be set to 20 ° C. or lower above the freezing point of the chemical solution. When the chemical solution is an aqueous solution, it may be 0 ° C. or higher and 20 ° C. or lower. It is preferably 0 ° C. or higher and 10 ° C. or lower.

Next, (d) a step 4 of reducing the pressure of the chemical solution to a pressure higher than the vapor pressure of the solvent of the chemical solution and lower than the atmospheric pressure is a requirement.
Decompression control is performed after (c) temperature control in the device, but if the air pressure in the device is lower than the vapor pressure of the solution when the pressure is reduced, the solution boils and the water in the solution volatilizes, which is not preferable. In order to remove oxygen to a higher degree under the condition that the solution is not boiled, it is preferable to reduce the pressure to a degree slightly higher than the vapor pressure at the temperature of the solution at that time. That is, it is preferable to reduce the pressure of the chemical solution to 1.01 times the vapor pressure of the solvent at the temperature. In the case of water, the vapor pressure at 20 ° C. is about 2,330 Pa, so the pressure is reduced to about 2,350 Pa. Here, the vapor pressure of water at 10 ° C. is 1,230 Pa, and the pressure is reduced to 1,240 Pa. Since the vapor pressure at 0 ° C. is about 610 Pa, the pressure is reduced to 620 Pa. Since the vapor pressure at −40 ° C. is about 20 Pa, the pressure is reduced to 21 Pa.
Further, the upper limit of the atmospheric pressure at the time of depressurization is preferably 5.0 times or less with respect to the vapor pressure of the solvent at the temperature of the chemical solution. When the pressure is reduced, the pressure of water, which is the solvent of the chemical solution, is reduced to 3 times or less the vapor pressure at the temperature, so that oxygen can be finally removed to a high degree. Therefore, (d) the range of decompression in step 4 in which the chemical solution is reduced to a pressure higher than the vapor pressure of the solvent of the chemical solution and lower than the atmospheric pressure is 1.01 times or more the vapor pressure of the chemical solution. The range is preferably 0 times or less. When it is desired to remove oxygen to a higher degree, the upper limit of the atmospheric pressure at the time of depressurization is preferably 3.0 times or less the vapor pressure of the solvent at the temperature of the chemical solution.

Next, the requirement is (e) step 5 of recovering the atmospheric pressure with an inert gas that does not substantially contain oxygen.
The inert gas is a gas that does not substantially contain oxygen and does not react with active ingredients, preparation additives, preparation components such as solvents, and preparation materials such as vials and rubber stoppers. The inert gas may be any gas as long as it does not cause any problem even if it diffuses into the environment and does not react with the solution components in the container, but it is preferable to use argon or nitrogen. The inert gas is preferably sterilized by a gas sterilization filter or the like. There is no limit to the inflow rate of the inert gas into the device as long as there is no effect such as the container in the device falling over or the half-stopped rubber stopper falling off.
After depressurization in the device, decompression with an inert gas is performed. The pressure at the time of recompression is preferably about atmospheric pressure.

The oxygen concentration in the device after recompression with the inert gas is highly removed, but it is possible that the dissolved oxygen in the solution has not been removed. When the container is sealed without removing the dissolved oxygen, a certain amount of the dissolved oxygen in the solution is transferred to the voids of the container as a gas, so that the oxygen concentration in the voids increases. Therefore, next, (f) the step 6 of allowing the chemical solution to stand in the inert gas atmosphere at a temperature equal to or higher than the freezing point of the chemical solution is required.
In order to remove the dissolved oxygen in the solution, it is essential to allow the container to stand for a certain period of time after repressurizing the inside of the device with an inert gas. By allowing the container to stand for a certain period of time in a device having a low oxygen partial pressure and a high inert gas partial pressure, the oxygen in the solution is transferred to the device space as a gas over time. Since the amount of dissolved oxygen in the solution is proportional to the partial pressure of oxygen, the amount of dissolved oxygen in the solution is greatly reduced if the oxygen in the apparatus is removed to a higher degree. It is considered that this step 6 contributes most to the reduction of the oxygen content of the solution preparation. Further, when the solution is frozen, it is necessary to set the temperature inside the apparatus to thaw, and the step 6 needs to be allowed to stand at a temperature equal to or higher than the freezing point of the chemical solution.

The time for allowing the chemical solution to stand in an inert gas atmosphere varies depending on the amount of the chemical solution filled and the temperature inside the apparatus. When the amount of the chemical solution is small, the time required for the dissolved oxygen in the chemical solution to become a gas and move into the space of the device is shorter than when the amount of the chemical solution is large. Further, when the temperature inside the apparatus is high, the temperature of the chemical solution becomes high and the solubility of oxygen in the chemical solution decreases, so that the time required for the dissolved oxygen to become a gas and move into the space of the apparatus becomes short. However, if the temperature of the chemical solution is too high, decomposition of the active ingredient due to heat and concentration change due to evaporation of water in the chemical solution may occur. Therefore, when the chemical solution is an aqueous solution, the temperature at which the chemical solution is allowed to stand in an inert gas atmosphere is preferably 0 ° C. to 40 ° C., more preferably 0 ° C. to 25 ° C.
If the standing time is 5 hours or more, more preferably 10 hours or more, it can be said that it is a sufficient time for the dissolved oxygen of the chemical solution to move into the space of the device.

A series of steps of temperature control, decompression control, repressure control, temperature control, and standing can be repeated as long as the container is not taken out of the apparatus and is kept in a sealed state. It is expected that the oxygen concentration will be further reduced by repeating.

Finally, the requirement is (g) step 7 of sealing the container containing the chemical solution under an atmosphere of an inert gas that does not substantially contain oxygen.
As described above, as a deoxidation operation, the temperature is controlled, the pressure is reduced, and then the pressure is restored with an inert gas, and the solution preparation that has been allowed to stand for a certain period of time is later sealed to ensure airtightness. .. In this step 7 operation, any sealing method may be used as long as oxygen does not flow into the apparatus and the container. Preferably, the container filled with the solution and semi-capped with a rubber stopper is decompressed with an inert gas in the apparatus via the oxygen removing method of the present invention, and then the top surface above the container is lowered. This is a method in which a rubber stopper is pushed into a container and sealed. Half-stopping means that the container is not completely sealed, there is a gap between the mouth of the container and the plug, and gas can enter and exit. The sealing operation in such a closed space can be achieved by a freeze-drying device having a plugging function used in the production of a usual pharmaceutical preparation for injection.

Since the pharmaceutical solution preparation is required to be a sterile preparation, it is preferable that the manufacturing apparatus used in the present invention can be sterilized. As a sterilization method for the device, a sterilization method using high-pressure saturated steam is preferable.
The operation steps of (A) temperature control, (B) decompression control, (C) repressure control by inert gas, and (D) sealing, which are the operation steps of the present invention, are the operations of ordinary manufacturing of pharmaceutical preparations for injection. It is performed by process operation and does not require special equipment. For example, the freeze-drying apparatus with a stoppering function used for producing a freeze-dried preparation is an apparatus capable of performing all the operations (A) to (D) in a sterile environment, and the production of the present invention. It is the preferred device for application to the method.

The pharmaceutical solution preparation according to the production method of the present invention can be produced by controlling the oxygen concentration per volume of the voids of the container to 0.5 (v / v)% or less. More preferably, it is 0.3 (v / v)% or less.
Oxygen in the gas in the void of the container can be measured by an oxygen concentration measuring device using an oxygen sensor. For example, using an oxygen densitometer (MicroxTX3, manufacturer: PreSens) connected to a needle-type oxygen sensor, the needle-type oxygen sensor is pierced into the rubber stopper of the preparation and brought into contact with the gas in the container to seal the product according to the present invention. The oxygen of the gas in the container in the state can be measured.
The pharmaceutical preparation prepared by the production method of the present invention can highly reduce the oxygen content in the unit preparation and suppress the production of related substances due to the presence of oxygen. For example, in the case of an aqueous solution containing pemetrexed disodium as an active ingredient, the amount of related substances produced according to the active ingredient after storage at 60 ° C. for 2 weeks is 0.5 (w / w)% or less.
The method for producing a pharmaceutical solution formulation of the present invention can produce a solution formulation with a highly reduced oxygen content in a unit formulation without using special equipment on an industrial scale. By introducing this manufacturing method into the manufacturing process of solution preparations, even active ingredients whose impurities tend to increase by reacting with oxygen in the solution state can maintain their efficacy and safety for a long period of time. It will be possible to provide.

Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.
[Example 1]
A glass vial with a capacity of 5 mL was filled with 4 mL of water, half-plugged with a rubber stopper, and placed on the shelf of a sealed device. The temperature of the shelf was set to 0 ° C., and after the water temperature in the vial reached 0 ° C., the pressure was reduced by a vacuum pump, and the air pressure in the sealed device was set to 1,000 Pa. After that, the vacuum pump was stopped, nitrogen gas was allowed to flow into the sealed device, and the pressure was restored. Then, the shelf was allowed to stand for 15 hours with the temperature of the shelf set to 0 ° C. After 15 hours, the shelves were lowered and plugged. After plugging, the temperature of the shelf was raised to about 20 ° C., and the plugged vial was taken out. The stoppered vial was wrapped with an aluminum cap.

[Example 2]
This is the same as in Example 1 except that a glass vial having a capacity of 30 mL was filled with 20 mL of water and the vial was allowed to stand at 0 ° C. for 38 hours after recompression with nitrogen.

[Example 3]
A glass vial with a capacity of 5 mL was filled with 4 mL of water, half-plugged with a rubber stopper, and placed on the shelf of a sealed device. The temperature of the shelf was set to −40 ° C., and after the water temperature in the vial reached −30 ° C. or lower, the pressure was reduced by a vacuum pump to set the air pressure in the sealed device to 50 Pa. After that, the vacuum pump was stopped, nitrogen gas was allowed to flow into the sealed device, and the pressure was restored. Then, the temperature of the shelf was set to 20 ° C., and the shelf was allowed to stand for about 10 hours. After 10 hours, the shelves were lowered, plugged, and taken out. The stoppered vial was wrapped with an aluminum cap.

[Example 4]
This is the same as in Example 3 except that a glass vial having a capacity of 30 mL was filled with 20 mL of water.

[Example 5]
This is the same as in Example 3 except that a glass vial having a capacity of 50 mL was filled with 30 mL of water.

[Comparative Example 1]
About 1000 mL of water was placed in a glass container having a capacity of 2 L, and nitrogen gas was blown into the liquid for 30 minutes with stirring to remove oxygen in the water and the glass container. The water was filled into a 5 mL vial with 4 mL. Nitrogen gas was blown into the filled vial and the vial was stoppered. The stoppered vial was wrapped with an aluminum cap.

[Comparative Example 2]
This is the same as in Comparative Example 1 except that a vial having a capacity of 30 mL was filled with 20 mL of water.

[Comparative Example 3]
A glass vial with a capacity of 5 mL was filled with 4 mL of water, half-plugged with a rubber stopper, and placed on the shelf of a sealed device. The temperature of the shelf was set to −45 ° C., and after the water temperature in the vial reached −40 ° C. or lower, the pressure was reduced by a vacuum pump to set the air pressure in the sealed device to 10 Pa. Then, the vacuum pump was stopped, nitrogen gas was allowed to flow into the sealed device, the pressure was restored, and then the shelf was lowered in a frozen state to stopper the stopper. Then, the temperature of the shelf was set to 20 ° C., and the water in the vial was taken out after shifting from the frozen state to the solution state. The removed vial was wrapped with an aluminum cap.

[Test Example 1] Measurement of Oxygen in Gas in Vial Void A oxygen concentration meter (MicroxTX3, manufacturer: PreSens) connected to a needle-type oxygen sensor was used. This has a fiber coated with a fluorescent dye (oxygen sensor) that is sensitive to oxygen at the tip of the needle, and the needle type oxygen sensor is inserted into the rubber stopper of the vials of Examples and Comparative Examples to keep the vial sealed. The oxygen concentration in the gas in the void was measured. The measurement results are shown in Table 1.

The oxygen concentration in the vial voids of Comparative Examples was about 0.5 (v / v)% to 1.0 (v / v)%, but the oxygen concentration in the voids in the vials of Examples 1-5. Was 0.09 (v / v)% to 0.22 (v / v)%. It was found that oxygen in the vial was highly removed by removing oxygen by the oxygen removing method according to the present invention. After repressurizing with an inert gas, the contents in the vial are made into a solution without plugging, and the vial is kept in a chamber with a high partial pressure of the inert gas and a low partial pressure of oxygen for several hours. It is probable that the dissolved oxygen in the solution became a gas and moved out of the vial by placing it.

An RTU-type solution preparation in which pemetrexed disodium was dissolved in water as an active ingredient was prepared, and the oxygen concentration and storage stability in the voids of the solution preparation were evaluated.
[Example 6]
Dissolve 1,510 mg of pemetrexed disodium salt 2.5 hydrate (1,250 mg in terms of pemetrexed) in an appropriate amount of water for injection, adjust the pH to 7.5 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution. Water for injection was added to make the total volume 50 mL.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with 4 mL of the filtered solution, and half-stopped with a rubber stopper. The vial was placed in a lyophilizer. The temperature of the shelf was set to 0 ° C., and after the contents in the vial reached 0 ° C., the pressure was reduced by a vacuum pump, and the air pressure in the sealed device was set to 1,000 Pa. After that, the vacuum pump was stopped, nitrogen gas was allowed to flow into the sealed device, and the pressure was restored. Then, the shelf was allowed to stand for 15 hours with the temperature of the shelf set to 0 ° C. After 15 hours, the shelves were lowered and plugged. After plugging, the temperature of the shelf was raised to about 20 ° C., and the plugged vial was taken out. The stoppered vial was wrapped with an aluminum cap.

[Example 7]
Dissolve 4,531 mg of pemetrexed disodium salt 2.5 hydrate (3,750 mg in terms of pemetrexed) in an appropriate amount of water for injection, adjust the pH to 7.2 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution. Water for injection was added to make the total volume 150 mL.
This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm, the vial was filled with 4 mL of the filtered solution, and half-stopped with a rubber stopper. The vial was placed in a closed device. The temperature of the shelf was set to −40 ° C., and after the contents in the vial reached −30 ° C. or lower, the pressure was reduced by a vacuum pump to set the air pressure in the sealed device to 50 Pa. After that, the vacuum pump was stopped, nitrogen gas was allowed to flow into the sealed device, and the pressure was restored. Then, the temperature of the shelf was set to 20 ° C., and the shelf was allowed to stand for about 10 hours. After 10 hours, the shelves were lowered, plugged, and taken out. The stoppered vial was wrapped with an aluminum cap.

[Comparative Example 4]
57.39 g of pemetrexed disodium salt 2.5 hydrate (47.5 g in terms of pemetrexed) was dissolved in an appropriate amount of 1,866 g of water for injection (total volume 1900 mL). The pH was adjusted to 7.2 with an appropriate amount of hydrochloric acid solution and an appropriate amount of sodium hydroxide solution. This solution was aseptically filtered using a membrane filter having a pore size of 0.22 μm. Nitrogen gas was blown into the solution for 30 minutes while stirring the solution to remove oxygen in the water and in the glass container. The solution was filled in a 5 mL vial with 4 mL. Nitrogen gas was blown into the filled vial and the vial was stoppered. The stoppered vial was wrapped with an aluminum cap.

[Test Example 2] Measurement of Oxygen in Gas in Vial Voids For the preparations of Example 6, Example 7, and Comparative Example 4, the same method as described above is used in the gas in the closed voids in the vial. Oxygen concentration was measured. The measurement results are shown in Table 2.

In Examples 6 and 7, the void oxygen concentration in the vial was 0.3 (v / v)% or less, indicating that oxygen was highly removed.

For the preparations of Examples 6 and 7 and Comparative Example 4, the properties, pH, and related substances (individual maximum (%), total amount (%)) of the preparations after storage at 60 ° C. for 2 weeks were evaluated.
[Test Example 3] Analytical conditions for pemetrexed-related substances The related substances derived from the decomposition of pemetrexed in Examples and Comparative Examples were analyzed under the following liquid chromatography (HPLC) conditions.
Column: GL Sciences Inertsil ODS-3 (inner diameter 4.6 mm, length 25 cm)
Column temperature: 40 ° C
Mobile phase A: Phosphate buffer (pH 6.8) / acetonitrile mixture (47: 3)
Mobile phase B: Acetonitrile liquid feed rate: 1.0 mL / min.
Wavelength: 225 nm
Mobile phase liquid feed: Liquid was fed under the conditions shown in Table 3.

Table 4 shows the evaluation results of the properties, pH, and related substances (individual maximum (%), total amount (%)) of the preparations of Examples 6 and 7 and Comparative Example 4 after storage at 60 ° C. for 2 weeks. .. The evaluation criteria were a pH of 6.6 to 7.8, an individual maximum of 0.2 (w / w)% or less of related substances, and a total amount of 1 (w / w)% or less of related substances.

Comparative Example 4 was colored deep yellow. Moreover, the individual maximum value of the related substance exceeded 0.2 (w / w)%. On the other hand, in Examples 6 and 7, although some coloring was observed after 2 weeks of storage at 60 ° C., the related substances were below the standard value. These storage stability results correlate with the void oxygen concentration in the formulation shown in Test Example 2, and the stability of the solution formulation is ensured by reducing the oxygen concentration in the formulation as much as possible. Became clear.
By producing a solution preparation using the oxygen removal method of the present invention, it is possible to highly remove oxygen in the solution preparation, and storage stability is possible even when the pharmaceutically active ingredient is unstable with respect to oxygen. It is considered that a solution preparation in which is guaranteed can be stably produced.

Claims (4)

A method for producing a sealed pharmaceutical solution preparation with a reduced oxygen content.
(A) Step 1 of preparing a chemical solution containing an active ingredient,
(B) Step 2 of injecting the chemical solution into a sealable container,
(C) Step 3 of lowering the chemical solution to 20 ° C. or lower
(D) Step 4 of reducing the pressure of the chemical solution to a pressure higher than the vapor pressure of the solvent of the chemical solution and lower than the atmospheric pressure.
(E) Step 5 of recovering the atmospheric pressure with an inert gas,
(F) Step 6 of exposing the chemical solution to the inert gas atmosphere at a temperature equal to or higher than the freezing point of the chemical solution for 5 hours or more and allowing it to stand.
(G) Step 7 of sealing the container containing the chemical solution under the atmosphere of an inert gas,
A method for producing a pharmaceutical solution preparation according to the above. (D) The method for producing a pharmaceutical solution preparation according to claim 1, wherein in step 4, the pressure is reduced to 1.01 times or more and 5.0 times or less the atmospheric pressure of the vapor pressure of the chemical solution. The first or second claim, wherein the chemical solution is filled with 50 (v / v)% or more of the volume of the container, and the oxygen concentration in the void of the container is 0.5 (v / v)% or less. Method for manufacturing pharmaceutical solution preparations. The method for producing a pharmaceutical solution preparation according to any one of claims 1 to 3 , wherein the active ingredient is pemetrexed disodium, which is an aqueous solution preparation containing water as a main solvent component.