JP6957233B2 - Stable injectable solution of pemetrexed - Google Patents

Description

The present invention relates to a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, and a method for producing the same.

Pemetrexed, N- [4- [2- (2-amino-4,7-dihydro-4-oxo-lH-pyrrolo [2,3-d] pyrimidin-5-, also known as pemetrexed diacid) Il) ethyl] benzoyl] -L-glutamic acid is a potent inhibitor of some folate-requiring enzymes and is useful in the treatment of non-small cell lung cancer and mesothelioma.
The currently commercially available product of pemetrexed (Alimta®) is available in the form of lyophilized powder. This form of pharmaceutical has some inconveniences, for example, the method of making these lyophilized products is complicated and expensive, and the reconstruction of the powder requires additional work steps, which is a work. The disadvantage is that it poses an undesired risk to the workers who perform the process and a risk of dilution errors. When pemetrexed is prepared as a concentrated solution that requires dilution prior to injection, pemetrexed is known to be stabilized by the use of antioxidants. An example of such a product is a 25 mg / ml pemetrexed concentrate for infusion with Caduceus Pharma Ltd / Actavis UK Ltd. Another concentrated solution product by Eagle Pharmaceuticals, awaiting USFDA approval, also with the help of cysteine hydrochloride as an antioxidant. Antioxidants are used to stabilize aqueous solutions of highly oxidized panite pemetrexed, but these such as antioxidants and other excipients such as amines, amino acids, solubilizers, complexants, etc. Excipients become extraneous agents and should be avoided as much as possible. Health authorities around the world are very interested in the levels of such extraneous agents in pharmaceutical compositions, especially pharmaceutical compositions for injectable / parenteral applications. Patients receiving chemotherapy are already facing the side effects of severe antitumor drugs and cannot tolerate even the slightest increase in side effects that these extraneous agents can cause, so pemetrexed For compositions comprising such anti-tumor agents, it is more desirable to avoid these agents. Avoiding these excipients and further achieving an injectable aqueous solution of pemetrexed with long-term stability is a challenge and an unmet requirement. Little attempts have been made to produce a concentrated sterile solution of pemetrexed while avoiding the presence of antioxidants, but with little success.

One such attempt has been made and is described in PCT International Publication No. 2012-121523 (hereinafter referred to as the '523 application). This provides a method for producing a pharmaceutical formulation in the form of an injectable antioxidant-free solution, wherein the method is pemetrexed or a method thereof by various deaeration methods such as (a) purging an aqueous medium or solution. It comprises controlling the concentration of dissolved oxygen in the injectable solution containing salt, and (b) filling the injectable container with the solution obtained from step (a) in the glove box. WO '523 discusses conventional sealing systems such as glove bags for controlling oxygen during filling operations. However, such a method using a sealing system such as a glove box during filling requires manual labor and is not suitable for large-scale commercial production of parenteral formulations in a GMP environment in a pharmaceutical factory. In addition, the defined compositions do not provide an injectable solution of pemetrexed with a dissolved oxygen level of 1 ppm or less and a dissolved oxygen level of 0-0.2 ppm. Therefore, it is necessary to develop a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof having the following characteristics.
・ Dissolved oxygen content of 0 to 0.2 ppm,
-Does not contain extraneous agents such as stabilizers (antioxidants) and solubilizers,
・ Long-term storage stability,
・ Guarantee of high sterility,
・ Large-scale commercial production is possible.

The present invention provides a stable, injectable aqueous solution of pemetrexed or a pharmaceutically acceptable salt thereof that meets these needs and has the desired characteristics described above. The present inventor uses a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof as a sterile solution having a dissolved oxygen level of 0 to 0.2 ppm, such as a stabilizer (antioxidant) and a solubilizer. A commercially suitable method has been developed for making the solution to give the solution free of extraneous agents. The solution is stable and when stored, the total impurities are less than 2.0% by weight after long-term storage.

The present invention is a stable injectable solution containing pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, which has a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, and is a stabilizer or a solubilizer. When placed in a container sealed with a stopper and stored at room temperature for 1 year, the total impurities in the injection solution do not increase to more than 2.0% by weight of pemetrexed. The injection solution is given.

The present invention is a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, which does not contain a stabilizer or a solubilizer and is sealed with a stopper. Further provided is a method for producing the injection solution contained in the container.

FIG. 5 is a graphic representation of a monopod stopper (Igloo stopper) having a flange portion “1” and a plug portion “2”. The plug portion has one groove "3" arranged radially and a vent position nib "4". FIG. 5 is a graphic representation of a bipod stopper having a flange portion "1" and a plug portion "2". The plug portion has a groove "3" arranged in the radial direction and a vent position nib "4". FIG. 5 is a graphic representation of a tripod stopper having a flange portion “1” and a plug portion “2”. The plug portion has a groove "3" and a vent position nib "4". It is a graphic representation of a conventional stopper having no groove according to the prior art having a flange portion "1" and a plug portion "2", the plug portion being solid and having no groove at all.

Known impurities include Impurity B, Impurity C, and Impurity F. Impurity B, as used herein, is a degrading impurity for pemetrexed, (2S, 2'S) -2,2'-[[(5R) -2,2'-diamino-4,4'. , 6-Trioxo-1,4,4', 6,7,7'-Hexahydro-1'H, 5H-5,6'-bipyrrolo 2,3-d] pyrimidin-5,5'-diyl] bis ( Ethylenebenzene-4,1-diylcarbonylimino)] It is chemically called dipentanedioic acid. The chemical structure of impurity B is as follows.

Impurity C, as used herein, is another degrading impurity of pemetrexed, (2S, 2'S) -2,2'-[[(5S) -2,2'-diamino-4, 4', 6-trioxo-1,4,4', 6,7,7'-hexahydro-1'H, 5H-5,6'-bipyrro [2,3-d] pyrimidine-5,5'-diyl ] Bis (ethylenebenzeneen-4,1-diylcarbonylimino)] It is chemically called dipentanedioic acid. The chemical structure of impurity C is as follows.

Impurity F, as used herein, is an oxidative impurity of pemetrexed and is chemically 4- {2-[(RS) -2-amino-4,6-dioxo-4,5,6. , 7-Tetrahydro-3H-pyrrolo [2,3-d] pyridimin-5-yl] ethyl} benzoyl) -L-disodium glutamate. Impurity F is generally known as ketopemetrexed and has the following chemical structure.

An assay for all impurities, chemicals, impurities B, impurities C, known impurities including impurity F, and a single unknown impurity is analyzed by suitable techniques such as high performance liquid chromatography (HPLC). In one embodiment, HPLC techniques are applied using a mobile phase (pH about 3.5) comprising a mixture of acetonitrile and ammonium formate buffer, and the chromatography column is C-8 ((150 × 4. 6) mm, 3.5 μ) column, chromatogram recorded using UV spectroscopy.

The term "stable," as used herein, when an injectable solution containing pemetrexed or a pharmaceutically acceptable salt thereof according to the invention is maintained at room temperature for at least one year. Is intended to mean having less than 2.0% by weight of total impurities of pemetrexed. When the solution of the present invention is stored at room temperature (15 ° C. to 30 ° C.) for 1 year or longer, the total impurities do not increase to more than 2.0% by weight of pemetrexed, preferably pemetrexed. 1.3% by weight or less, more preferably 1.0% by weight or less of pemetrexed.

The term "total impurities" as used herein refers to all known and unknown impurities of pemetrexed present in the injectable solution of the invention resulting from the decomposition of pemetrexed during the manufacture or storage of the finished product. Represents the total. All impurities are expressed as% by weight of pemetrexed, i.e.% by weight of labeled pemetrexed content.

The term "stable" means that the content of a single known impurity and the most unknown impurities in the solution during storage is the INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE. It can also mean that it is within the limits indicated by the United States Pharmacopeia or standards regulatory authorities such as the guidelines indicated by (ICH).

For example, when the solution is stored at room temperature for 1 year or more, the content of single impurities B and C is 0.24% or less, and the limit of single impurity F is 0.6% or less. The most abundant unknown impurities are 0.24% or less.

In addition, the injectable solution of the present invention is prepared when the change in the assay of pemetrexed during the production of the finished dosage form produced by the method described in the present invention is within ± 2%, that is, the assay is 98% to 102%. It can be said to be stable if it does not change beyond that. The injectable solution is also said to be stable when the pemetrexed assay remains within 90-110% of the labeled amount when stored at room temperature for extended periods in a container with a stopper.

The phrase "injectable" or "injectable solution", as used herein, means that the solution meets the criteria for parenteral products until the end of its shelf life, in particular that the solution has been sterilized. "Sterility", which means that the solution meets the requirements of standard pharmacopoeia, such as the United States Pharmacopeia (USP).

The phrase "without stabilizers or solubilizers", as used herein, means that the injectable solutions of the invention are excipients, complexing agents such as amino acids, amines, cyclodextrins, propylene glycol, polyethylene. It means that it does not contain cosolvents such as glycols, tremethylene glycols and butylene glycols, and additional excipients such as oily excipients such as mineral oils. The injection solution of the present invention is a sulfite antioxidant such as sodium metabisulfite, sodium sulfite, sodium bicarbonate, or other commonly used antioxidants such as thioglycerol, ascorbic acid, lipoic acid, propyl gallate. Does not contain antioxidants. It is preferable that the injectable solution of the present invention does not contain amino acids or amines such as cysteine, lysine, methionine, diethanolamine, tromethamine, meglumine and the like. It is preferable that the injection solution of pemetrexed does not contain a chelating agent such as disodium edetate, ethylenediaminetetraacetic acid, diethylenetriaminetetraacetic acid and the like.

The term "approximately" or "about", as used herein, means ± 10% of the value stated. When the term "about" is preceded by a pressure value, for example, "about X torr" preferably means a pressure of X ± 5% torr.

The pharmaceutically acceptable salts of pemetrexed that can be used in the present invention are, but are not limited to, sodium, disodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, monoethanol. Includes ammonium, triethanolammonium, tromethamine, pyridinium, substituted pyridinium and the like. Any suitable pharmaceutically acceptable salt of pemetrexed can be used, but the pharmaceutically acceptable salt is preferably the disodium heptahydrate salt of pemetrexed.

The amount or concentration of pemetrexed or a pharmaceutically acceptable salt thereof referred to in the present disclosure is expressed as an amount corresponding to the free acid form of pemetrexed. Pemetrexed or a pharmaceutically acceptable salt thereof is contained in a solution of the present invention in an amount ranging from about 2.0 mg / ml to about 100.0 mg / ml, preferably 20.0 mg / ml to about 50.0 mg / ml. For example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, It may be present in an amount ranging from about 20 mg / ml to about 30 mg / ml, such as 44, 45, 46, 47, 48, 49, or 50 mg / ml. In one embodiment, a disodium heptahydrate salt of pemetrexed is used, in an amount ranging from 20 mg / ml to 30 mg / ml (expressed as the amount corresponding to the free acid form of pemetrexed), eg, 25 mg / ml. Exists in.

The dissolved oxygen content in the injection solution according to the present invention is 0.2 million% (ppm) or less, that is, 0 to 0.2 million parts, for example, 0.01, 0.02, 0.03. 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0. 16, 0.17, 0.18, or 0.19 ppm. The dissolved oxygen content in the solution contained in the container can be measured by using a dissolved oxygen meter such as those commercially available under ^{the trademarks Seven GO TM} , Seven Duo Go Pro ^{TM (registered trademark-METTTLER TOREDO), or Winkler.} -Measurement can be performed by using other methods known in the art such as Azide titration method, method using diaphragm electrode (instrument analysis).

In one preferred embodiment, the dissolved oxygen concentration is measured using a dissolved oxygen meter (DO meter). A container containing the solution of the invention for which the dissolved oxygen concentration is measured is opened in a closed chamber with a nitrogen atmosphere (ie, having an oxygen concentration of less than 1 ppm) and the DO meter sensor is immediately placed in the sample (aqueous solution). Place and then press the READ button to start the measurement. The display shows the reading of the sample in either single channel or dual channel mode. The form of the endpoint indicating that the measurement is in progress is blinking. As soon as the measurement stabilizes, the stability icon appears and the result, the value of the dissolved oxygen concentration, is recorded.

The headspace oxygen present in the headspace of the vessel after filling with the injectable solution of pemetrexed is 1.0% v / v or less, preferably 0.5% v / v or less, such as 0.4, 0.3, 0. .2, 0.1, or 0% v / v, preferably 0.3% v / v or less, more preferably 0.2% v / v or less. Headspace oxygen levels can be determined by methods known in the art such as oxygen analyzers / electrical sensors (oxygen analyzers, MODEL 905V, Quantech Instruments), headspace gas chromatography, electrochemical analyzers, frequency modulation spectroscopy, fluorescence. It can be measured by a measurement method such as a quenching method or a quadrupole MS analyzer.

In one embodiment, headspace oxygen levels are measured by MODEL 905V by Quantek Instruments, a sensor-based oxygen analyzer. MODEL 905V is a low capacity sensor design. The oxygen sensor internal chamber through which the sample gas flows has a very small volume of about 0.1 cc. The sensor is located inside the device case near the front panel and connects to the front panel fitting vial 1/32 ID (0.3 inch) Inactive Tube to minimize tube length. The sensor vent port connects to a short narrow caliber tube for sample ejection and zero or calibration gas introduction. Headspace oxygen can be conveniently and conveniently measured in a short period of time according to this method. It is preferred that the needle be inserted into the male luer fitting of the sample probe used to pierce the headspace of the vial through the bulkhead of the vessel / vial. 1-2 cc of gas is withdrawn from the headspace of the vial using a plastic syringe connected via a sensor and a needle punctured into the bulkhead of the vial. This allows the headspace gas to enter the sensor through a needle or tube. A stable read is obtained in about 15 seconds. The analysis time per sample is about 30 seconds.

The injectable solution according to the invention may also contain parenterally acceptable excipients such as, but not limited to, osmotic or isotonic agents, pH regulators, buffers.

In one embodiment, an osmotic agent is used to adjust the tonicity of the solution to make the solution isotonic with parenteral / plasma fluid. The osmotic agents that can be used are selected from, but not limited to, sodium chloride, potassium chloride, mannitol, sorbitol, dextrose, sucrose and the like, or mixtures thereof.

The injectable solution has a pH in the range of 6-11, preferably about 7.0-8.0, eg, 7.05, 7.10, 7.15, 7.20, 7.25. 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, 7.65, 7.70, 7.75, 7.80, 7.85, 7. It has a pH of 90, or 7.95.

The pH of the solution can be adjusted within the desired range by the use of a pH regulator and, if necessary, a buffer can be used to maintain the pH within the range.

Acidity regulators and / or buffers that may be used include, but are not limited to, sodium hydroxide, potassium hydroxide, hydrochloric acid, sulfuric acid, acetic acid, sodium acetate, tartaric acid and the like, and mixtures thereof. In one preferred embodiment, the pH regulators are sodium hydroxide and hydrochloric acid. In one embodiment, the pH can be automatically adjusted within the desired range by the components present in the solution of the present invention.

The injectable solution of the present invention is placed in a container such as a vial, a bottle, a barrel of a prefilled syringe, and the like. In one embodiment, the container may be made of a hard material, such as glass, in particular a type I glass, which is silicate glass as specified in the United States Pharmacopeia Chapter <660>. Non-limiting examples of containers include glass vials, glass bottles, or glass barrels of prefilled syringes. Various filling volumes ranging from 1 ml to 100 ml of the solution, eg, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, Containers are filled with various filling volumes ranging from 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 ml, preferably 1 ml to 50 ml.

In a preferred embodiment, the container is a type I glass vial.

In one preferred particular embodiment, the container is a glass vial with a "blowback" mechanism, with radial notches inside the rim of the vial in the neck area to engage the notches or protrusions on the stopper.

In one preferred embodiment, the filling volume is 4 ml and the vial volume is 5 ml. In another preferred embodiment, the filling volume is 20 ml and the vial volume is 20 ml. In another preferred embodiment, the filling volume is 40 ml and the vial volume is 50 ml.

There can be different styles of vial neck blowback mechanisms. In one embodiment, the blowback mechanism is a US blowback style with an annular notch on the surface of the vial's plug seal.

In another embodiment, the blowback mechanism is a European style blowback with a vial neck widened under the sealing surface.

The vial blowback mechanism helps hold the stopper at the neck of the container when in a partially or half-plugged position, i.e. allows the stopper to fit tightly and evenly into the mouth of the vial. Maintains the position of the partially contained stopper by engaging with the nibs or rings present on the stopper, thereby helping to prevent the stopper from "jumping out" or "falling in" during the process. The blowback mechanism also helps to secure the airtight fit with the stopper when completely plugged, preventing the stopper from "popping out" before sealing.

In one embodiment, the container is plugged with an elastic closure or stopper.

The elastic closure or stopper is preferably a grooved stopper having one or more partial or complete grooves.

In particular, the stopper design is such that the stopper has a stopper plug portion having one or more grooves (the plug portion is represented by being labeled "2" in FIGS. 1, 2 and 3) and a flange portion (the plug portion is represented by being labeled "2"). It is designed to have (see the symbol "1" in FIGS. 1, 2 and 3). The flange portion has a larger diameter than the plug portion.

In one embodiment, the stopper has a one-sided groove or a radially arranged groove and is called an igloo stopper (FIG. 1). A grooved stopper having a one-sided groove in the plug portion is represented by adding "3" to FIG.

In another embodiment, the stopper has a two-sided groove or a radially arranged groove and is called a bipod stopper (FIG. 2). The two-sided groove of the plug portion of the stopper is represented by adding "3" to FIG.

In another embodiment, the stopper has a tripod groove and is called a tripod stopper (FIG. 3). The three-sided groove of the plug portion of the stopper is represented by adding "3" to FIG.

In one or more embodiments, the grooved stopper may have a plurality of grooves in the stopper plug portion.

The groove present in the body part allows gas exchange through the groove when the stopper plug is partially inserted into the mouth of the container, i.e. when the stopper is in a partially or half-plugged position. Allows communication between the external environment and the internal space of the container. The gas exchange rate between the vessel headspace and the external environment via a grooved stopper in a partially or half-plugged position is optimal as desired. The exchange rate is slower than the exchange rate when a grooveless stopper is placed in the vial.

The flange portion of the stopper is configured to cover over the mouth of the container and helps to seal the container when the plug portion of the grooved stopper is completely inserted into the mouth of the container.

In one embodiment, the stopper provides a passage for gas exchange in the container when the stopper is in a partially or half-plugged position, i.e., in an "upper" position. When the stopper is fully pushed into the mouth / neck of the container, i.e. below or in a lower position, the gap between the grooved stopper and the container is closed, i.e. the container is completely closed. Be plugged. At this position, no further exchange of gas or liquid can occur, i.e. a fluid-sealed fit is created at the interface between the stopper and the neck of the vial. In one embodiment, the stopper plug region may have a protrusion, also called a vent position nib, that projects outward (see symbolization "4" in FIGS. 1, 2, and 3). These nibs help hold the stopper at the neck of the container when the stopper is partially loaded into the mouth of the container. The vial blowback mechanism can be further helpful in holding the stopper at the neck of the vessel, i.e., when a two- or tripod stopper with a vent position nib is in the half-plugged position, firmly in the mouth of the vial. Allows it to fit evenly and prevents the stopper from "jumping out" or "falling in" during the process.

The stopper is preferably made of an elastomer material. Such elastomeric materials include, but are not limited to, rubber or other polymeric or plastic materials. In one embodiment, the stopper can be a bromobutyl or chlorobutyl elastomer rubber formulation.

In one preferred embodiment, the stopper has an oxygen permeability of 100 cc / m ² . Made of rubber material for 24 hours or less.

In one or more embodiments, the fully capped container is further sealed. In one embodiment, a cap can be used to permanently seal the container / vial. The cap can be a flip-off metal crimp-like cap, such as an aluminum cap, that can be crimped to the flange portion of the grooved stopper and the vial neck, thereby locking the stopper in place and permanently sealing the vial. ..

In one or more preferred embodiments, the container may be covered or packaged by a secondary container or packaging. The secondary container or packaging may preferably be a pouch, or bag, or film, or overlap, or carton that covers the container.

In one embodiment, the secondary container is a closed film. In one embodiment, the secondary container can be made of a material that provides light protection to the solution of pemetrexed and has oxygen, light, and moisture barrier properties. The materials that make up the secondary container include, but are not limited to, aluminum, or various polymers and copolymers such as polyamides, ethylene vinyl alcohol copolymers.

In one embodiment, the secondary packaging further comprises an oxygen scavenger. The oxygen scavenger can be placed in the space between the main container and the secondary container. In another preferred embodiment, the secondary container is a multi-layer overlap pouch with one layer made of oxygen scavenger material.

A stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof can be obtained by a particular method that allows large-scale commercial production of the product under Good Manufacturing Processes. In particular, these methods allow the production of large batch sizes of 100 liters to 2000 liters or more at high speeds. For example, stable injectable solutions of pemetrexed contained in containers of various sizes from 1 ml to 100 ml can be produced on a large scale by the methods of the present invention at speeds as high as 1000-10000 containers or more per hour. In one embodiment, a container with a filling volume of 5 ml can be produced on a large scale, on the order of 100,000 to 250,000 containers, at a rate of about 4000-10000 containers per hour. In another embodiment, a container with a filling volume of 5 ml can be manufactured on a large scale, on the order of 50,000 to 150,000 containers, at a rate of about 2500-5000 containers per hour.

On the other hand, the method described in the prior art uses a manually operated machine, such as a glove box, to manually fill one container / vial at a time. Such a method involving manual unit operation can only be performed on a small scale and is not suitable for large-scale production. Furthermore, it is important to note that the methods according to the invention can be carried out at room temperature and therefore no additional equipment is required to control the temperature, eg, to freeze or bring the temperature above room temperature. be.

The stable injectable solution of the present invention can be obtained by filling the container with a solution of pemetrexed, partially plugging it and placing it in a closed chamber. The closed chamber is subjected to a cycle in which the air pressure is reduced by applying a vacuum and then the pressure is released by the supply of an inert gas. The air pressure is reduced to a pressure in the range of about 100 torr, preferably 100 to 525 torr.

The method of obtaining the injectable solution of the present invention does not include an extreme drop in pressure, i.e. a drop to less than 100 torr, for example 30 torr or 50 torr. In the presence of a sharp drop in pressure, the inventor faced the undesired problem of loss of volume of injection solution. We do not want to be bound by any theory, but water loss occurs due to pressure drops below 80-100 torr. Volume loss or reduction results in an increase in the assay for pemetrexed in solution. Assays increase to above 2.0% and, in some cases, to above 4.0%, which exceeds the desired limit of 2.0% or less.

The steps of reducing the pressure within the optimum range and then releasing the pressure by the supply of an inert gas are usually performed at least twice, after which the half-capped filled container is completely capped and then In addition, the closed and filled container is sterilized by a known technique, preferably by autoclaving.

In one or more preferred embodiments, the method involves the additional step of holding the filled injection solution in a container inside a closed chamber for a period of one hour or longer. After the cycle of lowering the air pressure and releasing the pressure by the supply of the inert gas is over, it is preferable to carry out the step of holding. Following the step of holding the injectable solution filled in the container inside the closed chamber, the method may further accompany the step of reducing the air pressure (to a certain pressure) and releasing the pressure by the supply of an inert gas. Processing conditions and intermediate processing steps can vary. For example, the method can be changed by changing the target reduced air pressure, the cycle or repetition of the "reducing air pressure and then releasing pressure" step, or by changing the length of time the container is held in the chamber. ..

The chamber in which the partially plugged and filled container is placed is preferably a closed chamber with means for adjusting the air pressure. The chamber further has means for supplying the inert gas. In one embodiment, such a chamber is a lyophilizer with means for reducing the air pressure to about 80 to 560 torr. Such a chamber further has means of supplying an inert gas and using the inert gas to achieve a pressure of about 760 torr in the chamber. The inert gas that can be used preferably contains nitrogen, argon, neon, helium, or a mixture thereof. The container thus treated and filled is then sterilized by moist heat sterilization. This is done in an autoclave at a temperature of about 100 ° C. to 125 ° C. for a period of 5 to 60 minutes.

In one embodiment, the closed chamber is coupled with a vacuum pump that can be used to reduce the air pressure in the chamber to the desired value. In one embodiment, the closed chamber is coupled with an inert gas dispenser that can supply the closed chamber with an inert gas and help increase the pressure of the gas inside the closed chamber.

In one embodiment, there is a pressure sensor (pressure transmitter / Pirani vacuum gauge) that measures the pressure inside the chamber and helps monitor and maintain a given pressure while performing various operations. Various specific embodiments of the method for obtaining a stable injectable solution of pemetrexed of the present invention are described below.

In one embodiment, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm. The solution, which is free of agents or solubilizers and is contained in a container sealed with a stopper, is provided by a method comprising the following steps.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to 525 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated two or more times;
v. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In a particular embodiment, the step of applying reduced pressure (iii) is repeated two or more times so that the dissolved oxygen content of the solution is in the range of 0 to 0.2 ppm. Air pressure reduction can be achieved by applying a vacuum. The step of lowering the pressure and supplying the inert gas to the chamber to release the pressure (step iii) may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times. Is preferable.

The air pressure is in the range of about 100 torr, preferably about 100 to 525, for example 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160. , 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 276, 280. , 285, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 391, 395, 400, 405 , 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, or 525 torr. And so on. After this, the pressure is released by supplying an inert gas to achieve a normal / initial pressure of about 760 torr in the chamber. The pressure achieved after releasing the vacuum is typically about 760 torr, but this can vary. For example, the pressure can vary from 561 torr to 860 torr and above. A stopper with one or more grooves is an important feature for allowing gas exchange and implementing an instantaneous method when in a half-plugged position.

In one embodiment, step iii) is performed 2 to 10 times, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. Step iii) is preferably carried out 2 to 8 times, more preferably 3 to 6 times.

In another embodiment, step iii) is carried out at reduced air pressure of about 80-560 torr, preferably 100-525 torr, more preferably 100-275 torr.

In one or more embodiments, step iii) is repeated 2 to 10 times with reduced air pressure of 100 to 525 torr.

In one or more embodiments, step iii) is repeated 2 to 10 times with reduced air pressure of 100 to 275 torr.

In one or more embodiments, step iii) is repeated 4-10 times with reduced air pressure of 275-390 torr.

In one or more embodiments, step iii) is repeated 8-12 times with reduced air pressure of 391-525 torr.

In a preferred embodiment, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, and a stopper. When placed in a container sealed with, and stored at room temperature for 1 year, the total impurities in the solution do not increase to more than 1.0% by weight of pemetrexed and include the following steps: The injection solution produced by the above method is given.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100-275 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated two or more times;
v. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In some preferred embodiments, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm. When placed in a container sealed with a stopper and stored at room temperature for 1 year, the total impurities in the solution do not increase to more than 2.0% by weight of pemetrexed, and the following steps The injection solution produced by a method comprising.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 276 to 390 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated 4 times or more;
v. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In some preferred embodiments, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm. When placed in a container sealed with a stopper and stored at room temperature for 1 year, the total impurities in the solution do not increase to more than 2.0% by weight of pemetrexed, and the following steps The injection solution produced by a method comprising.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 391 to 525 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated 8 times or more;
v. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In one embodiment, a method of making a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof is provided, the method comprising the following steps.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to 525 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated two or more times;
v. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In one particular embodiment, step iii) is repeated twice with reduced air pressure of 100 torr. In one particular embodiment, step iii) is repeated 6 times with reduced air pressure of 100 torr.

In one particular embodiment, step iii) is repeated three times with reduced air pressure of 225 torr. In one particular embodiment, step iii) is repeated 4-5 times with reduced air pressure of 225 torr.

In one particular embodiment, step iii) is repeated 9 times with reduced air pressure of 525 torr. In one particular embodiment, step iii) is repeated 10 times with reduced air pressure of 525 torr.

In one or more embodiments, the method according to the invention repeats step (iii) followed by holding the container in a closed chamber for a period of one hour or longer, and optionally step (iii). It is preferable that and can be further included.

In one or more embodiments, the method comprises holding the container in a closed chamber for a period of one hour or longer after the step (iv), followed by repeating the step (iii) one or more times. Is preferable.

Surprisingly, the dissolved oxygen content in the solution ranges from 0 to 0.2 ppm if the method involves holding the container in a closed chamber for a period of 1 hour or more after the step (iv). It was measured that the inside was achieved by a relatively small number of repetitions of step (iii).

In one or more embodiments, when the method involves holding the container in a closed chamber, the dissolved oxygen content is relatively low as compared to when the method does not involve said step, but in both cases. In, the dissolved oxygen content is in the range of 0 to 0.2 ppm.

In one embodiment, a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, the stabilizer or solubilizing agent. The solution, which contains no agent and is contained in a container sealed with a stopper, is obtained by a method comprising the following steps.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step i) The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to 560 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated two or more times;
v. After step iv), the container is held in the closed chamber for a period of one hour or more, and step iii) is repeated as necessary;
vi. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In one embodiment, a method of making a stable injectable solution of pemetrexed or a pharmaceutically acceptable salt thereof is provided, the method comprising the following steps.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step i) The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to 560 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated two or more times;
v. After step iv), the container is held in the closed chamber for a period of one hour or more, and step iii) is repeated as necessary;
vi. The step of completely plugging the container and subjecting the container to moist heat sterilization.

The method is to repeat the step (iii) more than once with reduced air pressure of about 100-560 torr, to hold the container in a closed chamber for a period of 1 hour or more, preferably 2-20 hours, and the step (i). It may include steps having various combinations consisting of repeating either iii) or steps (iii) to (v) as needed as desired. The step (iii) is repeated two or more times, preferably three or more times. In one embodiment, step iii) is performed 2 to 10 times, eg, 2, 3, 4, 5, 6, 7, 8, or 9 times.

Step iii) is preferably carried out 2 to 8 times, more preferably 2 to 6 times.

In yet another embodiment, the step (iii) is carried out at a reduced air pressure of about 100-560 torr, preferably 100-525 torr, more preferably 100-390 torr.

In one or more embodiments, step (v) is performed for 1 hour or longer, preferably about 2-20 hours, eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, or 20 hours by holding the container in a closed chamber containing an inert gas.

In a preferred embodiment, the method according to the invention is a step of repeating step iii) more than once with reduced air pressure of about 100-560 torr, a container in a closed chamber for a period of 1 hour or longer, preferably 2-20 hours. The step iii) of repeating step iii) one or more times with a reduced air pressure of 100 to 560 torr is included, where the air pressure in step iii) performed after the holding step is retained. Same or different from the air pressure in step iii) performed before the step.

In another preferred embodiment, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm. Give the injection solution, which is free of stabilizers or solubilizers, is placed in a container sealed with a stopper and is prepared by a method comprising the following steps.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 to 390 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii repeated two or more times;
v. After the step (iv), the step of holding the container in the closed chamber for a period of one hour or more;
vi. Step of repeating step (iii) one or more times;
vii. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In some preferred embodiments, the present invention is a stable injectable solution comprising pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm. The injection solution, which is free of stabilizers or solubilizers and is contained in a container sealed with a stopper and is produced by a method comprising the following steps, is given.
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 390 torr 560 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step iii) is repeated 6 times or more;
v. After the step (iv), the step of holding the container in the closed chamber for a period of one hour or more;
vi. Step iii) is repeated one or more times;
vii. A step of completely plugging and sealing the container and subjecting the container to moist heat sterilization.

In one or more specific embodiments, the method repeats step iii) two or more times with reduced air pressure of 100 torr, then holds the container in a closed chamber containing an inert gas for a period of one hour or longer. The step iii) is repeated one or more times with a reduced air pressure of 100 to 525 torr.

In one or more specific embodiments, the method repeats step iii) twice with reduced air pressure of 100 torr, then holds the container in a closed chamber containing an inert gas for a period of 2-10 hours. The step v) is accompanied by the step v), and the step (iii) is repeated one or more times with the reduced air pressure of 100 torr.

In another particular embodiment, the method repeats step iii) three times with reduced air pressure of 100 torr, then holds the container in a closed chamber containing an inert gas for a period of 7 hours and 100 torr. It comprises repeating step iii) three times with reduced air pressure.

In yet another particular embodiment, the method repeats step iii) two or more times with reduced air pressure of 225 torr, then placing the container in a closed chamber containing an inert gas for a period of 2-20 hours. It comprises performing step v) with holding and repeating step iii) one or more times with reduced air pressure of 100-525 torr.

Further, in another embodiment, the method is to repeat step iii) four times with reduced air pressure of 225 torr, then hold the container in a closed chamber containing an inert gas for a period of about 2-20 hours. Contains.

In one particular embodiment, the method repeats step iii) four times with reduced air pressure of 225 torr, then holds the container in a closed chamber containing an inert gas for a period of about 6-20 hours. It comprises repeating step iii) three times with reduced air pressure of 225 torr.

In one particular embodiment, the method repeats step iii) three times with reduced air pressure of 225 torr, then holds the container in a closed chamber containing an inert gas for a period of about 2-10 hours. It comprises repeating step iii) twice with a reduced air pressure of 100 torr.

In one particular embodiment, the method repeats step iii) 6 times with reduced air pressure of 525 torr, then holds the container in a closed chamber containing an inert gas for a period of about 2-20 hours. It comprises repeating step iii) one or more times with reduced air pressure of 525 torr.

In one particular embodiment, the method repeats step iii 6 times with reduced air pressure of 525 torr, then holds the container in a closed chamber containing an inert gas for about 3 hours and 525 torr. It comprises repeating step iii) three times with reduced air pressure.

In one particular embodiment, the method repeats step iii) three times with reduced air pressure of 225 torr, then holds the container in a closed chamber containing an inert gas for about 3 hours, 100 torr. This includes repeating step iii) twice with the reduced air pressure.

In one particular embodiment, the method repeats step iii) three times with reduced air pressure of 100 torr, then holds the container in a closed chamber containing an inert gas for a period of 3 hours and 100 torr. It comprises repeating step iii) three times with reduced air pressure, then holding the container for 3 hours and repeating step iii) three times with reduced air pressure of 100 torr.

In one particular embodiment, the method repeats step iii) three times with reduced air pressure of 225 torr, then holds the container in a closed chamber containing an inert gas for a period of 3 hours and 225 torr. It comprises repeating step iii) three times with reduced air pressure, then holding the container for a period of 3 hours and repeating step iii) three times with reduced air pressure of 225 torr.

In some embodiments, the method involves repeating step iii) more than once with reduced air pressure of 80-560 torr, followed by holding in a closed chamber for more than 1 hour and repeating step iii). Includes performing a cycle.

When the injectable solution of pemetrexed of the present invention is stored at room temperature (15 ° C. to 30 ° C.) for 1 year, the total impurities in the solution do not increase until it exceeds 2.0% by weight of pemetrexed. , Known to be stable.

In a preferred embodiment, total impurities remain at 2.0% by weight or less of pemetrexed when the aqueous solution (contained in the container) is stored at room temperature for a period of up to 2 years or more.

In some preferred embodiments, total impurities remain at 1.3% by weight or less of pemetrexed when the aqueous solution (contained in the container) is stored at room temperature (15 ° C. to 30 ° C.) for a period of one year or longer.

In a more preferred embodiment, total impurities remain at 1.0% by weight or less of pemetrexed when the aqueous solution (contained in the container) is stored at room temperature (15 ° C. to 30 ° C.) for a period of one year or longer.

In addition, the content of a single known impurity and the most unknown impurities in the injectable solution is indicated by the INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH). It is within the limits indicated by the United States Pharmacopeia or standard regulators such as guidelines. For example, the injectable solution containing pemetrexed according to the present invention is stable, and is 0.24% or less when the solution of the present invention is stored at room temperature (15 ° C. to 30 ° C.) for a period of 1 year or more. It contains a single impurity B and C, a single impurity F of 0.6% or less, and the most unknown impurities of 0.24% or less.

Moreover, the change in the assay of pemetrexed during the manufacture of the finished dosage form produced by the method described in the present invention is within ± 2%, i.e. the assay does not change by more than 98% to 102%.

In addition, the pemetrexed assay is performed at room temperature (15 ° C. to 30 ° C.) for at least 1 year, preferably 1.5 years, more preferably 2 years, at 90.0% to 110.0% when the solution is stored. It stays well within the approval criteria, preferably within 95.0% to 105.0% of the label claims. Therefore, the injectable solution has long-term storage stability, especially at room temperature. In contrast, injectable solutions of pemetrexed with a dissolved oxygen content higher than 0.2 ppm, eg 0.32 ppm, were found to be unstable when stored for extended periods of time at room temperature. This is illustrated by the comparative example described below. Therefore, the present invention provided an injectable solution of pemetrexed having a dissolved oxygen content in the range of 0-0.2 ppm, which is robust and stable. The injectable solution is not only chemically stable, but can be implemented on a large scale and can be obtained by methods not limited to small-scale implementation using manual operation. Even more advantageous, the methods according to the invention do not require the use of deaeration methods such as the method of purging the medium or pemetrexed solution with an inert gas during the production of the solution.

As used herein, "contains" should be construed as "contains."

Aspects of the invention comprising specific elements are also intended to extend from related elements to alternative embodiments that "become" or "essentially".

Where technically appropriate, embodiments of the present invention may be combined.

Embodiments are described herein as comprising specific features / elements. The present disclosure extends to other embodiments consisting of or essentially consisting of said features / elements.

Technical documents such as patents and applications are incorporated herein by reference.

Any embodiment specifically and explicitly mentioned herein may form the basis of a claim to be excluded, either alone or in combination with one or more other embodiments.

Hereinafter, the present invention will be described in more detail as examples. The examples are not intended to limit the scope of the invention and are merely used as examples.

Example 1
According to a preferred embodiment of the invention, Examples illustrate a stable, injectable aqueous solution of pemetrexed in a glass container (vial).

The solution was prepared by the following method. Disodium heptahydrate salt of pemetrexed and sodium chloride were dissolved in water for injection. If the pH of the resulting solution is measured and the pH is found to be outside the range of 6.0-8.0, use a pH regulator such as sodium hydroxide and / or hydrochloric acid to bring it into this range. Adjusted. The solution of pemetrexed thus formed was filled in a glass container. The method was carried out at room temperature (25-30 ° C.). A glass container containing an aqueous solution of pemetrexed was partially or half-plugged using a grooved stopper. The partially plugged, filled container was then placed in a closed chamber with adjustable air pressure. In various batches, the pressure of the air in the chamber was reduced to a specific pressure value in the range of 100 torr 525 by applying a vacuum. The pressure was released by supplying an inert gas to the closed chamber until the pressure in the chamber reached a pressure of 760 torr. Two or more steps to reduce the pressure (application of vacuum) and supply the inert gas to the chamber, and / or dissolved oxygen levels (in solution) of less than 0.2 ppm and headspace of less than 0.5%. Repeated enough times to obtain the oxygen content of. The filled glass container was then completely plugged by firmly attaching the stopper to the glass container. The glass container was removed from the chamber and sealed using a flip-off aluminum crimping cap. The closed glass container was autoclaved at a temperature of about 121 ° C. for 15 minutes under moist heat sterilization.

Examples 2-9
A stable injection solution of pemetrexed was prepared as in the Examples, but by varying the treatment parameters as given in Table 2 below, and the dissolved oxygen content and changes in the pemetrexed assay were measured for injection. It was characterized by determining the volume loss of the solution.

Stability test: The pemetrexed solutions of Examples 4 and 5 contained in a glass vial and plugged with an Igloo grooved stopper were placed in a secondary packaging carton and then at room temperature (25 ° C., 60% relative humidity). ) And under the accelerated stability test conditions (40 ° C./75% relative humidity). The total impurities and the content of impurity F are given in Table 3 below.

Example 10

METHODS: Pemetrexed disodium heptahydrate salt and sodium chloride were dissolved in water for injection. If the pH of the resulting solution is measured and the pH is found to be outside the range of 6.0-8.0, use a pH regulator such as sodium hydroxide and / or hydrochloric acid to bring it into this range. Adjusted. The solution of pemetrexed thus formed was filled in a glass container, that is, a glass vial. Glass vials containing an aqueous solution of pemetrexed were half-plugged or partially plugged using a grooved igloo stopper. The partially capped, filled glass vials were then placed in a closed chamber maintained at room temperature (25-30 ° C.). The pressure of the air in the chamber was reduced to about 225 torr by applying a vacuum. The pressure was released by supplying an inert gas to the closed chamber until the pressure in the chamber reached a pressure of 760 torr. The step of reducing the pressure (application of vacuum) and supplying the inert gas to the chamber is repeated four times. After this, the vial was kept in a closed chamber for about 20 hours, then the step of reducing the pressure (to a pressure of 225 torr) and supplying the inert gas was repeated three times. The filled glass vial was then completely plugged by firmly attaching the stopper to the glass vial. The glass vial was removed from the chamber and sealed using a flip-off aluminum crimping cap. The sealed glass vials were autoclaved at a temperature of about 121 ° C. for 15 minutes under moist heat sterilization. Filled, sealed and autoclaved vials were covered with secondary packaging (carton).

Examples 11-15
Examples 11-15 follow a method similar to that described in Example 10, but the number of repetitions of the steps of changing the reduced air pressure in the target chamber, reducing the pressure and supplying the chamber with an inert gas. Illustrates a stable injectable solution of pemetrexed produced by varying the timing of holding the vial in a closed chamber. Dissolved oxygen levels and changes from the beginning in the pemetrexed assay were determined. Details are given in Table 5 below.

Stability test: Autoclaved vials obtained according to Example 10 (carton-covered, sealed, autoclaved vials) at various storage conditions, ie room temperature (25 ° C., 60% relative). Humidity), refrigerated conditions (temperature of 2-8 ° C.), and accelerated stability test conditions (40 ° C./75% relative humidity) were subjected to storage stability testing. The drug assay and the content of known and unknown impurities were analyzed at various points during storage. The content of all impurities and single impurities such as Impurity B, Impurity C, Impurity F, and the most unknown impurities was analyzed by HPLC or high performance liquid chromatography. The measurement results under various storage conditions are shown in Table 6 below.

Stability results (Table 6) show that an injectable aqueous solution of pemetrexed according to the present invention (Example 10) was at room temperature (25 ° C ± 2 ° C / 60% RH ± 5%) and at 2-8 degrees. It remained stable during long-term storage for more than 1 year in, indicating that total impurities were less than 1.0% by weight of pemetrexed during storage. Total impurities remained less than 1.0% by weight of pemetrexed, even when stored for 6 months under accelerated stability conditions of 40 ° C./75% relative humidity. Each of the single impurities, such as Impurity B, Impurity C, Impurity F, the most unknown impurities, and other known impurities, was less than 0.2% by weight. Assay values for pemetrexed remain largely unchanged upon storage, with values maintained in the range of 95% to 105%. In addition, the aqueous solution of pemetrexed remained physically stable, no precipitation or crystallization or color change occurred during storage, and the percentage value of the permeability of the solution remained above 95% during storage. Was measured.

Comparative Example 1
An injection solution of a comparative example of pemetrexed having a dissolved oxygen content of 0.32 ppm was prepared as follows. A solution of pemetrexed disodium heptahydrate salt and sodium chloride with a pH of 6.0-8.0 was made in water for injection and filled in a glass container, i.e. a glass vial. Glass vials containing an aqueous solution of pemetrexed were half-plugged or partially plugged using a grooved stopper and placed in a closed chamber maintained at room temperature (25-30 ° C.). The air pressure in the chamber was reduced to 225 torr by applying vacuum and then released to 760 torr by supplying an inert gas into the closed chamber. This step of reducing the pressure and releasing the pressure by supplying an inert gas to the chamber was performed only once and was not repeated. The filled glass vial was then completely plugged by firmly attaching the stopper to the glass vial. The glass vial was removed from the chamber and sealed using a flip-off aluminum crimping cap. The sealed glass vials were autoclaved at a temperature of about 121 ° C. for 15 minutes under moist heat sterilization. The dissolved oxygen content in the pemetrexed solution filled in the vial was measured and found to be 0.32 ppm.

Stability test: The autoclaved vial was kept in a carton and the storage stability test was continued under accelerated stability test conditions (40 ° C./75% relative humidity). The total impurities and the content of Impurity F were evaluated during initial and 2-month storage. The results are shown in Table 7 below.

It was measured that the total impurities increased significantly in just 2 months (until more than 1.0%). Moreover, the content of the impurity F increased remarkably until it became more than 0.2% in 2 months. In contrast to this, the total and known impurity F contents measured in the case of the pharmaceutical product produced according to the present invention in which the dissolved oxygen content is in the range of 0 ppm to 0.2 ppm were very low. {For example, refer to the stability measurement results of Examples 4 and 5 (Table 3) and Example 10 (Table 6)}. As is clear from the stability data given in Table 6 for Formulation Example 10, after 6 months of storage at 40 ° C./75% relative humidity, the total impurity content is only 0.48% (ie). It was less than 1.0%) and the impurity F was only 0.12 (ie less than 0.2%). Further, in the pharmaceutical product example 4 according to the present invention, after storage at 40 ° C./75% relative humidity for 2 months, the total impurity content is only 0.669 (that is, less than 1.0%), which is known. Impurity F was only 0.12 (ie less than 0.2%).

Comparative Example 2
An injectable solution of a comparative example of pemetrexed having a dissolved oxygen content of 1.45 ppm is prepared according to a known method of the prior art without the use of a grooved stopper and without a cycle of reducing and releasing the pressure. Use the grooveless rubber stopper shown in FIG. Details of the composition and method are given below.

A disodium heptahydrate salt of pemetrexed and an isotonic agent (mannitol) were dissolved in water for injection and then purged with argon gas. The pH of the resulting solution was adjusted to 7.2 using a pH regulator such as sodium hydroxide and / or hydrochloric acid. The solution of pemetrexed thus formed was aseptically filtered. The filtered bulk solution was purged with inert argon gas to reduce the dissolved oxygen level to less than 1 ppm. The solution (20 ml) was filled in a 20 ml glass vial. The headspace of the vial was flushed with argon gas and then the vial was plugged using a grooveless rubber stopper (FIG. 4). The stoppered vial was sealed with a flip-off aluminum crimping cap. The sealed glass vials were finally sterilized by subjecting them to moist heat sterilization in an autoclave at a temperature of 121 ° C. for 15 minutes. Filled, sealed and autoclaved vials were placed in a secondary packaging (carton).

Stability test: Sealed and autoclaved vials according to Comparative Example 2 under various storage conditions, ie, at room temperature (25 ° C, 60% relative humidity) and refrigerated conditions (temperature 2-8 ° C). , And a storage stability test under accelerated stability test conditions (40 ° C./75% relative humidity). Drug assays, the most unknown and total impurities, were analyzed at various storage points using HPLC or high performance liquid chromatography. The measurement results are given in Table 9 below.

The stability results show that the injectable aqueous solution of pemetrexed according to Comparative Example 2 having a dissolved content of> 0.2 ppm was at room temperature (25 ° C ± 2 ° C / 60% RH ± 5%) or at 40 ° C / 75%. It is shown that when stored under accelerated stability conditions of relative humidity, it exhibits substantially high total impurities and the formation of the most unknown impurities. However, after storage at room temperature for one month, total impurities exceed the desired limit of 2.0% by weight of pemetrexed, and the most unknown impurities exceed the desired limit of 0.24% by weight "less than or equal to" (. See Table 9). The assay value also goes down.

From the stability data of Comparative Examples 1 and 2 and Examples, it is clear that the dissolved oxygen content of 0 ppm to 0.2 ppm is significant in stabilizing the aqueous solution of pemetrexed and imparting long-term stability. be.

Claims (10)

A stable injectable solution containing pemetrexed or a pharmaceutically acceptable salt thereof, water for injection, having a dissolved oxygen content in the range of 0 ppm to 0.2 ppm, and containing no stabilizer or solubilizer. Put in a container sealed with a stopper,
The stopper is a grooved stopper having one or more partial or complete grooves.
The stable injectable solution, wherein all impurities in the solution do not increase until more than 2% by weight of pemetrexed when stored at room temperature for 1 year. It said container, made of rigid material, a stable injectable solution of claim 1. The stable injection solution according to claim 2, wherein the container is a glass vial and the design of the container includes a radial notch inside the edge of the vial in the neck region. The stable injectable solution of claim 1, wherein the container is packaged in a secondary container selected from a pouch, bag, film, overlap, or carton. The stable injection according to claim 1, wherein the solution in the container is subjected to a cycle of reducing the pressure and then releasing the pressure by supplying an inert gas, and then subject to moist heat sterilization. solution. The following steps:
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in the closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to about 275 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. A step in which step (iii) is repeated two or more times;
v. Steps of completely plugging and sealing the container and subjecting the container to moist heat sterilization,
The including method of a stable injectable solution of claim 1. The following steps:
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 276 torr to about 390 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step (iii) repeated 4 times or more;
v. Steps of completely plugging and sealing the container and subjecting the container to moist heat sterilization,
The including method of a stable injectable solution of claim 1. The following steps:
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 391 torr to about 525 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step (iii) repeated 8 times or more;
v. Steps of completely plugging and sealing the container and subjecting the container to moist heat sterilization,
The including method of a stable injectable solution of claim 1. The following steps:
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 100 torr to about 390 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. A step in which step (iii) is repeated two or more times;
v. After the step (iv), the step of holding the container in the closed chamber for a period of one hour or more;
vi. Step of repeating step (iii) one or more times;
vii. Steps of completely plugging and sealing the container and subjecting the container to moist heat sterilization,
The including method of a stable injectable solution of claim 1. The following steps:
i. A step of making a solution of pemetrexed or a pharmaceutically acceptable salt thereof in water for injection and filling the container with the solution;
ii. Step (i): The container is partially plugged with a grooved stopper having one or more grooves and placed in a closed chamber;
iii. A step of applying reduced air pressure of about 391 torr to about 560 torr to the closed chamber and then releasing the pressure by supplying an inert gas to achieve a pressure of about 760 torr;
iv. Step (iii) repeated 6 times or more;
v. After the step (iv), the step of holding the container in the closed chamber for a period of one hour or more;
vi. Step of repeating step (iii) one or more times;
vii. The vessel was sealed and completely stoppered, including the step of subjecting the container to wet heat sterilization method of a stable injectable solution of claim 1.

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