TWI476013B - Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection containing pemetrexed or its salt - Google Patents

Description

Method for preparing pharmaceutical formulation containing pemetrexed or its salt in the form of a solution without antioxidant injection

The present invention relates to a method for preparing a pharmaceutical formulation for a non-antioxidant injection solution containing pemetrexed or a salt thereof as an active ingredient thereof.

Pemetrexed or its salt (such as disodium salt) is an anti-folate anticancer agent with the chemical name N-[4-[2-(2-amino-4,7-di-4-oxo-1H-) Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzhydrazide]-L-glutamic acid, the chemical formula is as follows (U.S. Patent No. 5,344,932).

Pemetrexed or its salt is currently used for injection in the form of a lyophilized powder formulation. The lyophilized powder is first applied to a patient after being prepared, for example, as physiological saline. However, such a lyophilized powder preparation is produced through a complicated lyophilization procedure, so that the production cost is difficult to reduce. In addition, the clinic or hospital wants to administer the lyophilized powder preparation to the patient before it is prepared by physiological saline. This preparation step, in addition to inconvenience, also increases the risk of additional contamination.

Therefore, if pemetrexed or a salt thereof is formulated into an injectable preparation form, such as an injection solution, it can be conveniently used in a clinic or a hospital. However, pemetrexed is less stable in the injection vehicle (eg, water for injection) and may produce multiple degradation products. In order to solve this problem, International Patent Publication No. WO2001/56575 discloses a liquid preparation containing pemetrexed and an antioxidant such as thioglycerol, L-cysteine or ethanethiol. According to the disclosure of WO2001/56575, although general antioxidants such as sodium metabisulfite, ascorbic acid, sodium EDTA, ethanolamine gentisate, sodium formaldehyde sulfoxylate and sodium hydrogen sulfite do not provide desirable formulation properties, these three resistances Oxidizing agents (i.e., thioglycerol, L-cysteine, and ethanethiol) are useful in the preparation of stable liquid injectable formulations.

In addition, International Patent Publication No. WO 2010/30598 discloses a solid pharmaceutical formulation containing amorphous pemetrexed or a salt thereof and a process for the preparation thereof. International Patent Publication No. WO2001/62760 discloses the hexahydrate form of pemetrexed and a preparation method thereof. According to the disclosure of WO2001/62760, the water content of this heptahydrate form is more stable than the double hemihydrate.

The inventors of the present invention continuously researched and developed an injection-in-the-form pharmaceutical formulation having higher stability, and found that when dissolved oxygen in the injection solution is substantially removed by means such as degassing (that is, about 1 ppm or less), even if it is not added A stable liquid preparation containing pemetrexed or a salt thereof can also be prepared as a stabilizer such as an antioxidant.

Accordingly, the present invention provides a method for preparing a pharmaceutical formulation which is in the form of a solution for no antioxidant injection and which comprises pemetrexed or a salt thereof as an active ingredient.

According to the concept of the present invention, a method for preparing a pharmaceutical formulation for a non-antioxidant injection solution comprises: (a) controlling a dissolved oxygen concentration of an injection containing pemetrexed or a salt thereof to 1 ppm Or below; and (b) filling the solution obtained from step (a) into a container for injection in a closed system having a partial pressure of oxygen of 0.2% v/v or less.

In an embodiment of the present invention, the step (a) is performed by dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection having a dissolved oxygen concentration of 1 ppm or less, wherein the auxiliary drug system is A group consisting of sodium chloride, mannitol, and a pH control agent is selected. Further, in the present embodiment, both steps (a) and (b) are carried out in a closed system having a partial pressure of oxygen of 0.2% v/v or less.

In another embodiment of the present invention, the step (a) is an embodiment of dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection, wherein the auxiliary drug is selected from the group consisting of sodium chloride, mannitol, and A group consisting of a pH control agent; and then continuously charged with inert gas in the obtained solution to adjust the dissolved oxygen concentration to 1 ppm or less. In the present embodiment, the operation of continuously charging the inert gas is performed under a reduced pressure environment or in a vacuum.

The present invention finds that when the dissolved oxygen in the injection solution is substantially removed by means such as degassing or the like (that is, about 1 ppm or less), a stable pemetreme can be prepared even without adding a stabilizer such as an antioxidant. A liquid preparation of a plug or a salt thereof. Thus, the method of the present invention helps to reduce the use of adjuvants in the preparation of pharmaceutical products, thereby improving drug safety. In particular, the process of the present invention helps to avoid the production of any unknown degradation products by the use of antioxidants and also avoids the production of oxidative degradation products from the antioxidant itself.

The pharmaceutical formulation in the form of an injection is usually prepared by filling the ingredients in an ampoule or a glass bottle, and then replacing the ambient air present above the liquid with an inert gas such as nitrogen to improve stability during storage. Since pemetrexed is extremely stable in the injection medium (such as water for injection) and is prone to produce a variety of degradation products, it is necessary to use an antioxidant such as thioglycerol, L-cysteine or ethanethiol ( See WO2001/56575). In other words, only replacing the top gas with an inert gas such as nitrogen does not result in a stable pemetrexed injection preparation; therefore, specific antioxidants must be used to ensure the stability of the pemetrexed drug formulation. However, in terms of safety considerations, it is advisable to minimize the use of adjuvants when preparing pharmaceutical products. The present invention provides a method for preparing a stable injection form pharmaceutical formulation without using a stabilizer such as an antioxidant.

The present invention provides a method for preparing a pharmaceutical formulation for a non-antioxidant injection solution comprising: (a) controlling a dissolved oxygen concentration of an injection containing pemetrexed or a salt thereof to 1 ppm Or below; and (b) filling the solution obtained from step (a) into a container for injection in a closed system having a partial pressure of oxygen of 0.2% v/v or less.

The present invention finds that when the dissolved oxygen in the injection solution is substantially removed by means such as degassing or the like (that is, about 1 ppm or less), a stable pemetreme can be prepared even without adding a stabilizer such as an antioxidant. A liquid preparation of a plug or a salt thereof. Thus, the method of the present invention helps to reduce the use of adjuvants in the preparation of pharmaceutical products, thereby improving drug safety. In particular, the process of the present invention helps to avoid the production of any unknown degradation products by the use of antioxidants and also avoids the production of oxidative degradation products from the antioxidant itself.

Any known degassing method can be used in the process of the invention (see Table 1 below).

Two or more degassing methods can be used in combination. Examples of degassing methods used in combination include vacuum degassing and N ₂ degassing, vacuum degassing and film degassing, and degassing in combination with vacuum degassing and catalyst resin. In addition, the degassing method can be performed more than once.

In the method of the present invention, the concentration of dissolved oxygen is controlled relative to the water for injection or the solution obtained by dissolving pemetrexed or a salt thereof (along with the adjuvant) in water for injection. Those skilled in the art should be able to appropriately select the degassing method for the individual control method. For example, water for injection can be degassed by distillation with degassing and/or catalyst resin. Both the water for injection and the solution can be degassed by using a film, degassed under vacuum, and/or degassed with N ₂ .

In an embodiment of the present invention, the step (a) is an embodiment of dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection having a dissolved oxygen concentration of 1 ppm or less, wherein the auxiliary drug is selected A group consisting of free sodium chloride, mannitol, and a pH control agent. In this case, steps (a) and (b) are carried out in different or identical systems. That is, if steps (a) and (b) are carried out in the same system, both steps (a) and (b) can be carried out in a closed system having a partial pressure of oxygen of 0.2% v/v or less.

In another embodiment of the present invention, the step (a) is an embodiment of dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection, wherein the auxiliary drug is selected from the group consisting of sodium chloride, mannitol, and The group of pH controlling agents; and then continuously injecting inert gas (such as nitrogen or argon) into the obtained solution to adjust the dissolved oxygen concentration to 1 ppm or less. In the present embodiment, the operation of continuously charging the inert gas is performed under a reduced pressure environment or in a vacuum.

The salt of pemetrexed may be, for example, pemetrexed disodium, but is not limited thereto. Sodium chloride can be added as an isotonic agent, and mannitol can be added as an additive. In addition, a pH control agent such as sodium hydroxide or hydrochloric acid may also be added as needed.

The method of the present invention comprises the step of filling the injectable solution after the fungus into a container for injection, which may be, for example, an ampoule or a glass bottle. That is, the method of the present invention comprises filling the solution obtained in the step (a) in a container for injection in a closed system having a partial pressure of oxygen of 0.2% v/v or less.

The closed system having an oxygen partial pressure of 0.2% v/v or less is injected with an inert gas such as nitrogen or argon to adjust the oxygen partial pressure. For example, a conventional system such as a glove bag can be used as the closed system as described. When filling in the above closed system, the air at the top of the injection container is automatically replaced by inert gas.

The injectable pharmaceutical formulation of the present invention can be sterilized by conventional methods, for example, by means of a membrane filter and/or heat sterilization.

The content of the present invention will be described in detail with reference to the following examples and experimental examples. The examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the invention.

In the following examples, the dissolved oxygen concentration in the water for injection was measured using Winkler azide titration (modified sodium azide of the Winkler method) and a diaphragm electrode method (instrumental analysis). That is, the measured value is verified by the Winkler azide titration method after the measurement by the diaphragm electrode method. The dissolved oxygen concentration of the pemetrexed solution was measured only by the diaphragm electrode method. The method of measuring using a diaphragm electrode is as follows: (i) adding the sample to the BOD bottle before the calibration analysis; (ii) immersing the oxygen sensor in the BOD bottle containing the sample, the oxygen sensor being equipped with a stirring device, And the stirring device is connected to the dissolved oxygen measuring device; (iii) starting the dissolved oxygen measuring device; and (iv) waiting for about 5 minutes, and measuring the dissolved oxygen concentration after the sample dissolved oxygen concentration value in the BOD bottle is stabilized.

Example 1: Preparation of injection by distillation and degassing

700 ml of water for injection was heated and distilled in a nitrogen atmosphere with a heating mantle, and then cooled in a nitrogen atmosphere to remove dissolved oxygen therein. The dissolved oxygen concentration in the water for injection (degassed water) obtained was 0.5 ppm. The pemetrexed disodium (1.25 g is pemetrexed) and 0.45 g of sodium chloride were placed in a 100 ml glass container and the container was placed in a glove bag. Place the glass bottle, rubber cap and sterile filter together in the glove bag. The electrode of the pH meter is calibrated and cleaned and placed in a glove bag. Nitrogen gas was injected into the glove bag under reduced pressure to adjust the oxygen partial pressure to 0.1% v/v. 50 ml of degassed water was added to a 100 ml glass container in a glove bag by a syringe to dissolve the above ingredients. The pH measured in the glove bag was 7.66. The resulting solution was withdrawn by syringe and filtered through a 0.2 μm sterile filter attached to the syringe. Fill 4 ml of the 5 ml glass vial to obtain the filtrate, then seal the bottle with a rubber cap. Then open the glove bag and cover the glass bottle with an aluminum cover. The glass bottle was sterilized in a high pressure steam sterilizer for 15 minutes.

Example 2: Preparation of injection by vacuum degassing

Add pemetrexed disodium (2.5 g for pemetrexed) and 0.9 g of sodium chloride to a 250 ml glass vial with a gas inlet and a vacuum outlet, and add 100 ml of water for injection. The above ingredients are dissolved. The dissolved oxygen concentration of the water for injection was 6.5 ppm. Connect nitrogen to the gas inlet and connect the diaphragm vacuum pump to the vacuum outlet. Repeat the vacuum degassing operation and the nitrogen flushing operation. A portion of the resulting solution was taken to measure the dissolved oxygen concentration and pH. According to the measurement results, the solution had a dissolved oxygen concentration of 0.8 ppm and a pH of 7.68.

The resulting solution was drawn with a syringe and placed in a glove bag. Place the glass bottle, rubber cap and sterile filter together in the glove bag. Nitrogen gas was injected into the glove bag under reduced pressure to adjust the oxygen partial pressure to 0.1% v/v. The solution was aspirated with a syringe and the solution was filtered through a 0.2 μm sterile filter attached to the syringe. Fill 4 ml of the 5 ml glass vial to obtain the filtrate, then seal the bottle with a rubber cap. Then open the glove bag and cover the glass bottle with an aluminum cover. The glass bottle was sterilized in a high pressure steam sterilizer for 15 minutes.

Comparative example 1

Pemetrexed disodium sulphate (1.25 g is pemetrexed) and 0.45 g of sodium chloride were dissolved in 50 ml of degassed water for injection. The dissolved oxygen concentration and its pH were measured separately. According to the measurement results, the pH of the solution was 7.68, and the dissolved oxygen concentration in the solution was 6.4 mg/L (6.4 ppm). The resulting solution was filtered through a 0.2 μm sterile filter. Fill 4 ml of the 5 ml glass vial to obtain the filtrate, then seal the bottle with a rubber cap.

Comparative example 2

Pemetrexed disodium sulphate (1.25 g is pemetrexed) and 0.45 g of sodium chloride were dissolved in 50 ml of degassed water for injection. The dissolved oxygen concentration and its pH were measured separately. According to the measurement results, the pH of the solution was 7.67, and the dissolved oxygen concentration in the solution was 6.4 mg/L (6.4 ppm). The resulting solution was drawn with a syringe and placed in a glove bag. Place the glass bottle, rubber cap and sterile filter together in the glove bag. Nitrogen gas was injected into the glove bag under reduced pressure to adjust the oxygen partial pressure to 0.1% v/v. The solution was aspirated with a syringe and the solution was filtered through a 0.2 μm sterile filter attached to the syringe. Fill 4 ml of the 5 ml glass vial to obtain the filtrate, then seal the bottle with a rubber cap. Then open the glove bag and cover the glass bottle with an aluminum cover.

Experimental example: stability test

The stability of the preparation of the injectable solution in the above examples and comparative examples was measured under pressure conditions (75 ± 2 ° C, relative humidity 85 ± 5%). The amount of pemetrexed and degradation products was measured by a known method using a high performance liquid chromatography (HPLC) as described in the literature (Chromatographia 2007, 66, pp. 431-434). The stability test results for seven days under pressure conditions are shown in Table 2 below.

As shown in Table 2, in Comparative Examples 1 and 2 using an injectable solution (prepared with water for injection without adjustment of dissolved oxygen), if the solution for injection was stored under pressure for one week, even without autoclaving Disinfection, it was also observed that significant appearance changes and increased degradation products were observed. On the other hand, in the solutions for injection according to Examples 1 and 2 of the present invention, even after high-pressure steam sterilization, the formation of degradation products was 0.1% or less and was not measured. The above results demonstrate that the injectable solution of the present invention has excellent stability.

Claims (5)

A method for preparing a pharmaceutical formulation in the form of a non-antioxidant injection solution, and the method comprises: (a) controlling a dissolved oxygen concentration of an injection containing pemetrexed or a salt thereof 1 ppm or less; and (b) in a closed system having a partial pressure of oxygen of 0.2% v/v or less, the solution obtained from the step (a) is filled into an injection container. The method of claim 1, wherein the step (a) is performed by dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection having a dissolved oxygen concentration of 1 ppm or less. Wherein the adjuvant is selected from the group consisting of sodium chloride, mannitol, and a pH control agent. The method of claim 2, wherein the steps (a) and (b) are carried out in a closed system having a partial pressure of oxygen of 0.2% v/v or less. The method of claim 1, wherein the step (a) is performed by dissolving pemetrexed or a salt thereof and at least one auxiliary drug in water for injection, wherein the auxiliary is selected from the group consisting of chlorination A group consisting of sodium, mannitol, and a pH control agent; and then continuously inert gas is added to the obtained solution to adjust the dissolved oxygen concentration to 1 ppm or less. The method of claim 4, wherein the act of continuously charging the inert gas is performed under a reduced pressure environment or in a vacuum.