KR20130122065A - Stabilized aqueous preparation for injection containing pemetrexed - Google Patents

Abstract

The present invention relates to a stabilized liquid formulation for injection, containing pemetrexed or a pharmaceutically acceptable salt thereof and, more specifically, to a liquid formulation containing pemetrexed for injection with improved stability, containing sodium sulfide and/or sodium sulfite as a stabilizer. [Reference numerals] (AA) Injection solution;(BB) Ascorbic acid

Description

STABILIZED AQUEOUS PREPARATION FOR INJECTION CONTAINING PEMETREXED}

The present invention relates to a stabilized injectable liquid formulation containing pemetrexed or a pharmaceutically acceptable salt thereof, more particularly sodium sulfide or sodium sulfite as stabilizer. It relates to a pemetrexed-containing injectable liquid formulation having improved stability by including at least one stabilizer selected from sulfite).

Compounds known to have certain antifolate activities are well known as chemotherapy agents for the treatment of cancer. US Patent No. 5,344,932 describes a process for the preparation of certain substituted pyrrolo [2,3-d] pyrimidine based antifolate derivatives, including pemetrexeds, and European Patent Publication No. 0434426. 4-hydroxypyrrolo [2,3-d] pyrimidine-L-glutamic acid derivatives are known.

Pemetrexed is a 5-substituted pyrrolo [2,3-d] pyrimidine, a metabolite that is involved in folate metabolism in various carcinomas, including non-small cell lung cancer. It is a multitargeted antifolate that exhibits anticancer efficacy by inhibiting activity.

Pemetrexed is introduced into cells through a reduced folate carrier (RFC), which is a major cellular pathway of folic acid, and then polyglutamate by folylpolyglutamate synthetase (FPGS). Thymidylate synthase (TS) and dihydrofolate reductase (DHFR).

Currently, seed alrimta peme Trek ^® (ALIMTA ^®) has been developed as a brand name that has been marketed as a remedy for the treatment of malignant pleural mesothelioma and non-small cell lung cancer (Physicians' Desk Reference, 60th ed ., Pp. 1722-1728 (2006) Reference). Alta ^® is a form of lyophilized preparation which must be reconstituted prior to administration, i.e. lyophilized powder which must be reconstituted with 0.9% sodium chloride solution upon administration to the patient and finally diluted (0.25 mg / ml final concentration) with 0.9% sodium chloride solution. (100 or 500 mg) in the form of commercially available.

Formulations in the form of lyophilized powders are complex to manufacture and costly to process. In addition, there is a risk of contamination by microorganisms during the reconstitution of the lyophilized formulation, and the pharmacists, doctors, nurses, and the like who are involved are likely to be exposed to cell-destructive substances, and thus formulations that pose a threat to safety.

Thus, there is a need for the development of ready-to-use liquid formulations that can improve safety. The development of ready-to-use liquid formulations is particularly necessary for highly toxic anti-tumor substance products such as pemetrexed, and several formulations have been proposed that can overcome the above drawbacks.

In the prior art, US Pat. No. 5,716,988 discloses ready-to-use parenteral oxaliplatinum preparations comprising an aqueous solution of oxaliplatinum. In addition, International Patent No. W01999 / 043355 is a stable oxaliplatin solution formulation comprising a therapeutically effective amount of oxaliplatin, a stabilizing effective amount of a buffer and a pharmaceutically acceptable carrier, wherein the buffer comprises an oxaliplatin solution formulation which is oxalic acid or an alkali metal salt thereof. It is starting. In particular, US Pat. No. 6,686,365 (Korean Patent Publication No. 10-2002-0081293) is a stable pemetrexed solution formulation comprising an effective therapeutic amount of pemetrexed, a stabilizing effective amount of antioxidant and a pharmaceutically acceptable excipient. In addition, the antioxidant has been reported liquid pemetrexed formulation comprising an antioxidant selected from the group consisting of monothioglycerol or L-cysteine or thioglycolic acid.

However, pemetrexed or its pharmacologically acceptable salts, which are used for the treatment of malignant pleural mesothelioma and for the treatment of non-small cell lung cancer, are unstable when prepared in aqueous solution and thus cannot be stored for a long time at room temperature. For this reason, the pemetrexed preparation was developed and sold only as a solid preparation, which is a lyophilized formulation prepared in solution at the time of use.

The inventors conducted a stability test after preparation of a liquid formulation containing pemetrexed including the above-mentioned antioxidants, and as a result, the softening material started to increase from three months of acceleration and did not maintain stability for a desired period of use. I couldn't.

The present inventors have conducted studies to overcome the above problems, and when sodium sulfide or sodium sulfite is contained, the present inventors can effectively reduce or exclude the generation of the flexible substance pemetrexed isomer and unknown flexible substance. It has been found that it is possible to provide a liquid formulation for injection containing pemetrexed that is stable during the storage period in the state of a clear solution without precipitation.

The present invention contains pemetrexed which can stably store pemetrexed in aqueous solution for a long period of time (about 2 years or more) by containing sodium sulfide or sodium sulfite as a stabilizer. It is aimed at developing liquid preparations for injection.

Accordingly, the present invention provides a pemetrexed-containing injectable liquid formulation containing pemetrexed or a pharmaceutically acceptable salt thereof as an active ingredient, sodium sulfide or sodium sulfite as a stabilizer and a pharmaceutically acceptable carrier. It aims to do it.

The present invention comprises as an active ingredient pemetrexed or a pharmaceutically acceptable salt thereof at a concentration of 1 to 100 mg / ml and comprises 0.4 × 10 ⁻⁶ M to 0.1 × 10 ⁻⁴ M sodium sulfide or 0.2 × 10 A pemetrexed-containing injectable liquid formulation is provided comprising at least one stabilizer selected from ^-6 M to 0.8 x 10 ^-5 M sodium sulfite and a pharmaceutically acceptable carrier.

The present invention can provide a liquid formulation for injection containing pemetrexed that is easy to manufacture commercially, prevents microbial contamination during lyophilization or reconstitution, and has improved dosage convenience and stability.

Figure 1 compares the stability of water for injection with a conventional stabilizer added.
Figure 2 shows the stability test results of the pemetrexed-containing liquid formulation according to the present invention carried out under the conditions of 40 ℃ / 75% (4M) and 60 ℃ / 80% (4W), respectively.

The present invention comprises a pemetrexe as an active ingredient containing pemetrexed or a pharmaceutically acceptable salt thereof and containing at least one stabilizer selected from the group consisting of sodium sulfide or sodium sulfite and a pharmaceutically acceptable carrier. Seed containing liquid formulations for injection are provided.

The concentration of said pemetrexed or pharmaceutically acceptable salt thereof in the present invention is about 1-100 mg / mL, preferably 20-50 mg / mL.

Stabilizers used in conventional general injectable preparations include parahydroxybenzoic acid ester derivatives, alcohols, phenol derivatives, thimerosal and acetic anhydride. Sodium carboxylate, lauryl sulfate, antioxidants, sulfide compounds, sulfite, cystine, cystein, cysteamine organic acids such as cysteamine, amino acids, ascorbic acid, retinol, tocopherol, and butyl hydroxyl anisole.

Korean Patent Publication No. 10-2003-0021935 discloses N-acetyl amino acid as a stabilizer of paclitaxel, and Korean Patent Publication No. 10-2007-0028331 discloses monothioglycerol and ethylene diamine tetraacetic acid of diclofenac composition. It is disclosed as a stabilizer.

However, in the present invention, stability is not improved when the above-described general stabilizer is added. Storage stability test was confirmed that when the ascorbic acid, lactic acid and the like used in a number of common injections among the stabilizers these solutions partially showed acid instability such as discoloration and precipitation (Fig. 1).

Surprisingly, in the present invention, when an antioxidant such as sodium sulfide or sodium sulfite is used as a stabilizer, the active ingredient is not substantially changed for a long period of time (about 2 years or more) at a temperature of 1-30 ° C. and no discoloration or deposit occurs. It has been found that liquid formulations for injection containing stabilized pemetrexed that meet the criteria can be provided.

Sodium sulfide and sodium sulfite as stabilizers for imparting stability are described in the US Pharmacopeia 34 National Formulary 29 (Rockville, MD 20852) 1669 and 4258, respectively. .

Particularly preferred stabilizers are sodium sulfide. Concentration in the solution of sodium sulfide is 0.1 × 10 ^-6 M to about 0.4 × 10 ^-4 M, and preferably, 0.4 × 10 ^-6 M to 0 .1 × 10 ^-4 M are more preferred.

In addition, when sodium sulfite is used as a stabilizer, the concentration of sodium sulfite in the solution is preferably 0.8 × 10 ^-7 M to 0.8 × 10 ^-4 M, and 0.2 × 10 ^-6 M to 0.88 × 10. ^-5 M is more preferred.

When the stabilizer is added below or above the concentration range, the formation of the flexible substance increases under the same conditions, thereby reducing the stabilization effect.

In the present invention, the pharmaceutically acceptable carrier is water for injection.

The pH of the pemetrexed-containing injectable liquid formulation of the present invention is preferably about 5-11, about 7-10. The pH of the solution can be adjusted using an acid (eg hydrochloric acid) and a base (eg aqueous sodium hydroxide solution).

The pemetrexed-containing injectable liquid formulation of the present invention does not need to include other additives in addition to such stabilizers, but may further include a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include known additives such as lactose, dextrose, cyclodextrin and derivatives thereof, sucrose, glycerol, sodium carbonate, and the like, and preferred excipients include sodium chloride and mannitol.

In preparing the formulations of the present invention, purge with an inert gas (eg nitrogen or argon) to maintain hypoxic conditions, followed by sterile filtration.

In addition, the stabilized pemetrexed-containing injectable solution of the present invention may be packaged in a suitable container known in the art. For example, suitable containers may be glass vials, vials, cartridges, pre-filled injections and the like, preferably glass vials.

The formulations are dispensed in pre-washed sterilized containers and the surface of the stopper suitable for the container is sealed with a Teflon stopper that is inert to the aqueous solution of pemetrexed. If necessary, the space between the solution and the stopper is filled with an inert gas. After the stopper is attached using a crimper, the vial filled with the liquid formulation is heat sterilized if necessary.

Hereinafter, the present invention will be described in detail by way of examples. However, the scope of the present invention is not limited by these examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example

Example  1-8: As a stabilizer Sodium Sulfide  Containing Pemetrexed  Preparation of Containing Injectable Solution

Sodium sulfide was added to 100 ml of water for injection at the concentration shown in Table 1 to completely dissolve it. 2.5 g of pemetrexed was slowly added thereto, mixed until the solution became clear, and then stirred while filling with nitrogen gas. This solution was sterile filtered with a sterile 0.22 μm filter in a sterile chamber. The resulting solution was filled into a washable, sterile, sealable container.

The components and pH of the obtained pemetrexed-containing injectable solution are shown in Table 1 below.

Active ingredient
density
(mg / mL) Stabilizer Type Stabilizer concentration
(M) pH Example 1 25 Sodium sulfide 0.2 × 10 ^-6 7.85 Example 2 25 Sodium sulfide 0.1 × 10 ^-5 8.38 Example 3 25 Sodium sulfide 0.4 × 10 ^-5 9.99 Example 4 25 Sodium sulfide 0.1 × 10 ^-4 10.61 Example 5 25 Sodium sulfide 0.4 × 10 ^-4 11.18 Example 6 25 Sodium sulfite 0.2 × 10 ^-5 8.24 Example 7 25 Sodium sulfite 0.8 × 10 ^-5 8.59 Example 8 25 Sodium sulfite 0.2 × 10 ^-4 8.83

Example  9-12: Pemetrexed  Preparation of Injectable Solution at Different Concentrations

To the composition and content of Table 2 below, a solution for injection containing pemetrexed was prepared in the same manner as in Example 1, and a pH regulator (0.1 N HCL) was used if necessary.

Active ingredient concentration
(mg / mL) Stabilizer Type Stabilizer concentration
(M) pH Example 9 12.5 Sodium sulfide 0.4 × 10 ^-5 7.25 Example 10 25 Sodium sulfide 0.4 × 10 ^-5 7.36 Example 11 50 Sodium sulfide 0.4 × 10 ^-5 7.39 Example 12 100 Sodium sulfide 0.4 × 10 ^-5 7.6

Comparative Example  1-10: by type of antioxidant Pemetrexed  Preparation of Injectable Solutions

To the composition and content of Table 3 below, a solution containing pemetrexed was prepared in the same manner as in Example 1. Comparative Example 1 is a solution containing only water for injection as a carrier without adding a stabilizer.

Active ingredient concentration
(mg / mL) Stabilizer Type Stabilizer Concentration
(M) pH Comparative Example 1 25 - - 7.53 Comparative Example 2 25 Ascorbic acid 0.1 × 10 ^-5 6.48 Comparative Example 3 25 Sodium thiosulfate 0.1 × 10 ^-5 7.54 Comparative Example 4 25 Butyl hydroxyl anisole 0.1 × 10 ^-5 9.87 Comparative Example 5 25 Propyl gallate 0.1 × 10 ^-5 9.54 Comparative Example 6 25 EDTA 0.8 × 10 ^-6 6.77 Comparative Example 7 25 L-cystine 0.2 × 10 ^-5 7.45 Comparative Example 8 25 N-acetyl cysteine 0.2 × 10 ^-5 6.36 Comparative Example 9 25 L-histidine 0.2 × 10 ^-5 7.63 Comparative Example 10 25 L-methionine 0.2 × 10 ^-5 7.44

Test Example  1: Stability test

The composition prepared in Examples 1 to 8 was subjected to a stability test at 40 ° C./75% for 4 months and 60 ° C./80% for 4 weeks. The content of the pemetrexed remaining in the aqueous solution and the flexible material were performed under the same conditions as in Table 4 using the high-performance liquid chromatography method, and the results are shown in Tables 5 and 6 below.

column Agilent zorbax SB-C8, 150 * 4.6 mm, 3.5 um Detector UV Absorbance Photometer (250nm) Mobile phase Gradient way
Mobile phase A-acetic acid buffer solution; acetonitrile (97: 3)
Mobile phase B-acetic acid buffer solution; acetonitrile (87.5: 12.5)
Acetic acid buffer solution (0.03 mol / L, pH 5.5): To 2 L of water, add 3.4 M of acetic acid (100) and stir, adjust the pH to 5.5 with 50% sodium hydroxide. Flow rate 1 mL / min Column temperature 35 ℃ Analysis time 55 minutes

(1) Severe Stability Results (60 ° C / 80%, 4 Week Stability Evaluation)

Stability evaluation Active ingredient
density
(mg / mL) Stabilizer
Kinds Stabilizer
Concentration (m) pH content
(%) softness
matter
(%) Total flexibility
matter
(%) Example 1 25 Sodium sulfide 0.2 × 10 ^-6 7.85 Early 99.84 0.04 0.16 2 weeks 99.09 0.23 0.91 4 weeks 98.17 0.57 1.83 Example 2 25 Sodium sulfide 0.1 × 10 ^-5 8.38 Early 99.86 0.03 0.14 2 weeks 99.06 0.22 0.94 4 weeks 98.63 0.33 1.37 Example 3 25 Sodium sulfide 0.4 × 10 ^-5 9.99 Early 99.88 0.02 0.12 2 weeks 99.72 0.06 0.28 4 weeks 99.28 0.11 0.72 Example 4 25 Sodium sulfide 0.1 × 10 ^-4 10.61 Early 99.79 0.09 0.21 2 weeks 99.61 0.08 0.39 4 weeks 99.48 0.08 0.52 Example 5 25 Sodium sulfide 0.4 × 10 ^-4 11.18 Early 99.63 0.27 0.37 2 weeks 99.34 0.28 0.66 4 weeks 99.24 0.25 0.76 Example 6 25 Sodium sulfite 0.2 × 10 ^-5 8.24 Early 99.85 0.02 0.15 2 weeks 99.06 0.36 0.94 4 weeks 98.7 0.41 1.3 Example 7 25 Sodium sulfite 0.8 × 10 ^-5 8.59 Early 99.86 0.05 0.14 2 weeks 99.15 0.34 0.85 4 weeks 99.05 0.37 0.95 Example 8 25 Sodium sulfite 0.210 ^-4 8.83 Early 99.91 0.03 0.09 2 weeks 99.12 0.43 0.88 4 weeks 99.14 0.38 0.86

Evaluation of stability by concentration of principal components Active ingredient
density
(mg / mL) Stabilizer
Kinds Stabilizer
Concentration (m) pH content
(%) softness
matter
(%) Total flexibility
matter
(%) Example 9 12.5 Sodium sulfide 0.4 × 10 ^-5 7.25 Early 99.84 0.04 0.16 2 weeks 99.28 0.16 0.72 Example 10 25 Sodium sulfide 0.4 × 10 ^-5 7.36 Early 99.84 0.05 0.16 2 weeks 99.29 0.1 0.71 Example 11 50 Sodium sulfide 0.4 × 10 ^-5 7.39 Early 99.86 0.05 0.14 2 weeks 99.63 0.09 0.37 Example 12 100 Sodium sulfide 0.4 × 10 ^-5 7.6 Early 99.86 0.05 0.14 2 weeks 99.32 0.2 0.68

Stability evaluation Active ingredient concentration
(mg / mL) Stabilizer
Kinds Stabilizer concentration
(M) pH content
(%) softness
matter
(%) Total flexibility
matter
(%) Comparative Example 1 25 - - 7.53 Early 99.93 0.01 0.07 2 weeks 99.21 0.33 0.79 4 weeks 97.9 0.66 2.1 Comparative Example 2 25 Ascorbic acid 0.1 × 10 ^-5 6.48 Early 99.3 0.63 0.7 2 weeks 98.99 0.6 1.01 4 weeks Not measurable
(discoloration) - - Comparative Example 3 25 Sodium thiosulfate 0.1 × 10 ^-5 7.54 Early 99.81 0.04 0.19 2 weeks 99.69 0.24 0.61 4 weeks 98.27 0.72 1.73 Comparative Example 4 25 Butyl hydroxyl
Anisole 0.1 × 10 ^-5 9.87 Early 99.74 0.1 0.26 2 weeks 98.66 0.45 1.34 4 weeks Not measurable
(discoloration) - - Comparative Example 5 25 Propyl gallate 0.1 × 10 ^-5 9.54 Early 99.58 0.11 0.42 2 weeks 97.42 1.03 2.68 4 weeks Not measurable
(discoloration) - - Comparative Example 6 25 EDTA 0.8 × 10 ^-6 6.48 Early 97.38 0.53 2.62 2 weeks 97.03 1.23 2.97 4 weeks Not measurable
(discoloration) - - Comparative Example 7 25 L-cystine 0.2 × 10 ^-5 7.45 Early 99.8 0.05 0.2 2 weeks 99.05 0.38 0.95 4 weeks 98.18 0.71 1.82 Comparative Example 8 25 N-acetyl
Cysteine 0.2 × 10 ^-5 6.36 Early 99.5 0.11 0.5 2 weeks 98.44 0.18 1.56 4 weeks Not measurable
(discoloration) - - Comparative Example 10 25 L-methionine 0.2 × 10 ^-5 7.39 Early 99.85 0.05 0.15 2 weeks 99.09 0.35 0.91 4 weeks 98.68 0.51 1.32

As can be seen in Table 7, in the case of the injection solution containing a pemetrexed containing no stabilizer or using a general stabilizer, it is found that the solution is very unstable due to a large increase in impurities, for example, an isomer of a flexible substance. Could.

(2) Accelerated Stability Results (40 ° C / 75%, 4 Months Stability Evaluation)

Stability evaluation Active ingredient
density
(mg / mL) Stabilizer
Kinds Stabilizer
Concentration (m) pH content
(%) softness
matter
(%) Total flexibility
matter
(%) Example 3 25 Sodium sulfide 0.4 × 10 ^-5 9.99 Early 99.88 0.02 0.12 2 months 99.68 0.08 0.32 4 months 99.47 0.16 0.53 Example 4 25 Sodium sulfide 0.1 × 10 ^-4 10.61 Early 99.79 0.09 0.21 2 months 99.52 0.15 0.48 4 months 99.19 0.23 0.81 Example 5 25 Sodium sulfide 0.4 × 10 ^-4 11.18 Early 99.63 0.27 0.37 2 months 99.26 0.28 0.74 4 months 98.53 0.37 1.47 Example 7 25 Sodium sulfite 0.8 × 10 ^-5 8.59 Early 99.85 0.02 0.15 2 months 99.52 0.12 0.48 4 months - - -

Stability evaluation Active ingredient
density
(mg / mL) Stabilizer
Kinds Stabilizer
Concentration (m) pH content
(%) softness
matter
(%) Total flexibility
matter
(%) Comparative Example 1 25 - - 7.53 Early 99.93 0.01 0.07 2 months 99.89 0.04 0.11 4 months 98.52 0.6 1.48 Bagyo Example 2 25 Ascorbic acid 0.1 × 10 ^-5 6.48 Early 99.3 0.63 0.7 2 months 98.93 0.94 1.07 4 months 98.7 0.52 1.3 Comparative Example 3 25 Thiosulfate
salt 0.1 × 10 ^-5 7.54 Early 99.81 0.04 0.19 2 months 98.09 0.36 1.91 4 months 96.63 0.91 3.37 Comparative Example 4 25 Butyl hydroxyl anisole 0.1 × 10 ^-5 9.87 Early 99.74 0.1 0.26 2 months 98.09 0.74 1.91 4 months Not measurable
(discoloration) - Comparative Example 5 25 profile
Gallate 0.1 × 10 ^-5 9.54 Early 99.58 0.11 0.42 2 months 95.57 1.93 4.43 4 months Not measurable
(discoloration) - - Comparative Example 7 25 L-cystine 0.2 × 10 ^-5 7.45 Early 99.8 0.05 0.2 2 months 98.43 0.45 1.57 4 months Not measurable
(discoloration) - - Comparative Example 8 25 N-acetyl
Cysteine 0.2 × 10 ^-5 6.36 Early 99.5 0.11 0.5 2 months 98.18 0.2 1.82 4 months Not measurable
(discoloration) - Comparative Example 10 25 L-methionine 0.2 × 10 ^-5 7.39 Early 99.85 0.05 0.15 2 months 99.55 0.15 0.45 4 months 97.9 0.66 2.1

As can be seen in Table 8, when sodium sulfide is used as a stabilizer, the concentration is 0.4 × 10 ⁻⁴ M, which is relatively excessive. On the contrary, when the concentration of sodium sulfide was 0.4 × 10 ⁻⁵ M or less or 0.1 × 10 ⁻⁴ M or less, or when sodium sulfite having a suitable concentration was used as a stabilizer, the content change and the impurity generation were less than 1.5%.

As a result, it can be seen that the formulation according to the embodiment of the present invention shows an excellent stability in the formation of the flexible material compared to the comparative example.

Claims (6)

It contains 1-100 mg / ml pemetrexed or a pharmaceutically acceptable salt thereof as an active ingredient, and contains 0.1 × 10 ⁻⁶ M to 0.4 × 10 ⁻⁴ M sodium sulfide or 0.8 × 10 A stabilized pemetrexed-containing injectable liquid formulation, characterized in that it comprises at least one stabilizer selected from ^-7 M to 0.8 x 10 ^-4 M sodium sulfite and a pharmaceutically acceptable carrier. The method of claim 1,
A pemetrexed-containing injectable liquid formulation, characterized in that the content of said pemetrexed or pharmaceutically acceptable salt thereof is 20-50 mg / mL. The method of claim 1,
Pemerexide-containing injectable liquid formulation, characterized in that the stabilizer is 0.4 × 10 ^-6 M to 0.1 × 10 ^-4 M sodium sulfide. The method of claim 1,
A pemetrexeside-containing injectable liquid formulation, wherein the stabilizer is 0.2 × 10 ⁻⁶ M to 0.8 × 10 ⁻⁵ M sodium sulfite. The method of claim 1,
A pemetrexed-containing injectable liquid formulation, characterized in that it is contained in a sealed container ready-to-use. The method of claim 5,
The container is a pharmaceutical glass vial, wherein the stopper surface in contact with the inside of the glass vial is sealed with a stopper inert to the pemetrexed-containing injectable liquid formulation.

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