KR100913063B1 - Oxaliplatin-containing parenteral solution - Google Patents

Abstract

The present invention relates to (a) 1 × 10 ⁻⁴ M to 1 × 10 ⁻³ M acetic acid, (b) 1 × 10 ⁻⁵ M to 1 × 10 ⁻² M citric acid and 1 × 10 ⁻⁵ M to 1 × 10 ^-2 M ammonium oxalate, and (c) from 1 x 10 ^-4 M to 1 x 10 ^-2 M acetic acid and 1 x 10 ^-4 M to 1 x 10 ^-2 M ammonium oxalate Selected stabilizers; Oxaliplatin; And a pharmaceutically acceptable carrier, an oxaliplatin-containing injectable solution.

Oxaliplatin-containing injectable solutions of the present invention contain certain concentrations of acetic acid, citric acid and ammonium oxalate, or acetic acid and ammonium oxalate as stabilizers, thereby effectively reducing the generation of lead B, E, C and unknown lead. Or may be excluded.

Oxaliplatin, stabilized

Description

Oxaliplatin-containing parenteral solution

The present invention relates to a stable oxaliplatin-containing injectable solution.

Oxaliplatin is a third-generation platinum-based anticancer agent, its chemical name is cis-oxalato (trans-l-1,2-diaminocyclohexane) platinum (II), and its optical isomer, cis-oxalato (trans) -d-1,2-diaminocyclohexane) platinum (II) and any racemic mixture thereof. In addition, the "oxaliplatin" is cis-oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) having high optical purity, that is, 99.5% or more, for example US Patent No. 5,338,874 Cis-oxalato (trans-1-1,2-diaminocyclohexane) platinum (II) having a melting point of 198 ° C. to 292 ° C., obtained as disclosed in US Pat. No. 5,420,319 Cis-oxalato (trans-l-1,2-cyclohexanediamine) platinum (II) having a purity of at least 99.94% and a melting point of 198.3 ° C to 199.7 ° C. Oxaliplatin is a cytostatic antineoplatic agent useful for the treatment of many types of tumors, including colon cancer, ovarian cancer, bronchial cancer, epidermal cancer and germ cell cancer, and its preparation, physical properties and pharmaceutical properties are US patents. 4,169,846, 5,290,961, 5,298,642, 5,338,874, 5,420,319, 5,716,988, and European Patent Application No. 715854.

Oxaliplatin has a solubility in water of about 6 mg / mL, and various impurities such as diaqua DACH platinum, diaquo DACH platinum dimer, and platinum (IV) are gradually dissolved in an aqueous solution. It is known to decompose into, and this degradation product is a major cause of toxicity in oxaliplatin preparations. Therefore, the development of a formulation capable of preventing or minimizing the formation of such degradation products in long term storage over 1-2 years is a very important task.

Currently, oxaliplatin has been developed as a product called ELOXATIN ™ and marketed as a treatment for advanced colorectal cancer and metastatic gastric cancer. Eloxatin ™ is commercially available in the form of a lyophilized formulation that must be reconstituted prior to administration, reconstituted with water for injection or 5% glucose solution and finally diluted with 5% glucose solution (0.2 mg / ml final concentration) immediately prior to administration to the patient. Lyophilized powder (50 or 100 mg).

Lyophilized Eloxatin ™ may have several disadvantages. The lyophilization process is relatively complex and expensive to manufacture, and in order to use the lyophilized product, the product must be reconstituted in use, and there may be an error in selecting a solution suitable for such reconstitution. For example, in the reconstitution of lyophilized Eloxatin ™, the misuse of the 0.9% NaCl solution, a common solution for reconstitution or liquid dilution of lyophilized products, results in precipitation as well as loss of oxaliplatin. Works. Reconstitution of lyophilized products also increases the risk of microbial contamination in sterile products that do not require reconstitution, and lyophilized products fail to sterilize in comparison to solution products sterilized by filtration or heating (final) sterilization. There is a greater risk of this, and in some cases undesirable particles are produced upon reconstitution. These lyophilized products are likely to be exposed to contamination by workers, pharmacists, doctors, nurses, and others involved in manufacturing and reconstitution, which are very serious because of the toxicity of antitumor substances.

The development of a solution of ready-to-use (RTU) oxaliplatin will significantly reduce the risks associated with the preparation and reconstitution of lyophilized formulations. Several formulations have been proposed to meet the need for oxaliplatin solution formulations in the form of RTUs that can overcome the above drawbacks.

For example, US Pat. No. 5,716,988 discloses oxaliplatin formulations for parenteral administration comprising an aqueous solution of oxaliplatin having a concentration of 1-5 mg / ml and a pH in the range of 4.5-6. In addition, WO 1999/043355 (Republic of Korea Patent Publication No. 2001-0041182) 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 is oxalic acid or An oxaliplatin solution formulation which is an alkali metal salt thereof is disclosed. In addition, WO2003 / 047587 (Korean Patent Publication No. 10-2005-0058278) discloses a stable oxaliplatin solution formulation comprising oxaliplatin, a stabilizing effective amount of lactic acid and a pharmaceutically acceptable salt thereof. In addition, WO 2005/020980 (Korean Patent Publication No. 10-2007-0022184) discloses a pharmaceutical liquid formulation for parenteral administration of stable oxaliplatin using tartaric acid or a salt thereof as a stabilizer.

The inventors have sought to develop an oxaliplatin-containing injectable solution in the form of ready-to-use (RTU) while having stability for a long period of time (about 2 years or more), resulting in specific concentrations of acetic acid, citric acid and Or, if acetic acid and ammonium oxalate are used as stabilizers, analog B ((SP-4-2) -diaqua [(1R, 2R) -cyclohexane-1,2-diamine-κN, κN '] platinum (diaquodiaminocyclohexaneplatinum)) , Analog E ((SP-4-2) -di-μ-oxobis [(1R, 2R) -cyclohexane-1,2-diamine-κN, κN '] diplatinum (diaquodiaminocyclohexaneplatinum dimer)), analog C (( OC-6-33)-[(1R, 2R) -cyclohexane-1,2-diamine-κN, κN '] [ethanedioato (2-)-κO ¹ , κO ² ] dihydroxyplatinum) and unknown lead compounds It has been found that it can be effectively lowered or excluded.

It is therefore an object of the present invention to provide an oxaliplatin-containing injectable solution containing a certain concentration of acetic acid, citric acid and ammonium oxalate, or acetic acid and ammonium oxalate as stabilizers.

According to one aspect of the invention there is provided (a) 1 × 10 ⁻⁴ M to 1 × 10 ⁻³ M acetic acid, (b) 1 × 10 ⁻⁵ M to 1 × 10 ⁻² M citric acid and 1 × 10 ^{− 5} M to 1 × 10 ⁻² M ammonium oxalate, and (c) 1 × 10 ⁻⁴ M to 1 × 10 ⁻² M acetic acid and 1 × 10 ⁻⁴ M to 1 × 10 ⁻² M ammonium oxal Stabilizers selected from the group consisting of late rates; Oxaliplatin; And a pharmaceutically acceptable carrier, an oxaliplatin-containing injectable solution is provided.

Oxaliplatin-containing injectable solutions of the present invention contain certain concentrations of acetic acid, citric acid and ammonium oxalate, or acetic acid and ammonium oxalate as stabilizers, thereby effectively reducing the generation of lead B, E, C and unknown lead. Or may be excluded. In particular, the generation of lead B, C and unknown lead substances can be lowered to 0.4% or less, 0.1% or less, or 0.2% or less, respectively, and the generation of lead E can be completely excluded, and the US Food and Drug Administration (FDA) Stabilized oxaliplatin-containing injection solution can be provided that meets the criteria.

Oxaliplatin-containing injectable solutions of the present invention contain certain concentrations of acetic acid, citric acid and ammonium oxalate, or acetic acid and ammonium oxalate as stabilizers, thereby effectively reducing the generation of lead B, E, C and unknown lead. Or may be excluded. That is, it is possible to reduce the occurrence of the flexible substances B, C and unknown flexible substances to 0.4% or less, 0.1% or less, 0.2% or less, respectively, and to completely eliminate the generation of the flexible substance E, so that the US Food and Drug Administration (FDA) Stabilized oxaliplatin-containing injection solution can be provided that meets the criteria.

In particular, in contrast to the disclosures of WO 1999/043355 (Korean Patent Publication No. 2001-0041182) and WO 2003/047587 (Korean Patent Publication No. 2005-0058278), acetic acid is used as a stabilizer. It is surprising that even with use, stable oxaliplatin-containing injectable solutions can be prepared. In addition, the fact that stable oxaliplatin-containing injectable solutions can be prepared even when acetic acid and ammonium oxalate are simultaneously used as stabilizers is very surprising given the disclosure of the prior art. For reference, according to the stability test results (Table 2) of WO1999 / 043355, it is disclosed that it is not preferable to use citric acid or acetic acid as a stabilizer, and in Example 1 of WO2003 / 047587 Table 1 also discloses that citric acid and acetic acid are not suitable as stabilizers.

In the oxaliplatin-containing injection solution of the present invention, when acetic acid is used as a stabilizer, the concentration of acetic acid in the solution is more preferably 1 × 10 ⁻⁴ M to 1 × 10 ⁻³ M. In addition, when citric acid and ammonium oxalate are used as stabilizers, the concentrations in the solution of citric acid and ammonium oxalate are 1 × 10 ^-5 M to 1 × 10 ^-2 M and 1 × 10 ^-5 M to 1 × 10, respectively. ^-2 M is preferred. In addition, when acetic acid and ammonium oxalate are used as stabilizers, the concentrations in the solutions of acetic acid and ammonium oxalate are 1 × 10 ⁻⁴ M to 1 × 10 ⁻³ M and about 1 × 10 ⁻⁴ M to 1, respectively. More preferred is ^10-3 M.

In the oxaliplatin-containing injectable solution of the present invention, the oxaliplatin contained as an active ingredient may be contained in the range of 1 to 7 mg / ml, preferably 2 to 5 mg / ml.

Such pharmaceutically acceptable carriers are water or additional excipients (eg, ethanol, glycerin, propylene glycol, and polyoxyethylene glycol) that are soluble / miscible in water, and additional excipients that provide isotonicity of the formulation (e.g., , Dextrose or saline). The carrier is preferably water, more preferably sterile water for injection.

The pH of the oxaliplatin-containing injectable solution of the present invention is about 2 to about 6, preferably about 3 to about 5.

The oxaliplatin-containing injectable solution of the present invention can be prepared by preparing an aqueous carrier comprising the stabilization described above and dissolving the oxaliplatin in the obtained carrier.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example  One. As a stabilizer  Containing acetic acid Oxaliplatin Preparation of Solutions

Acetic acid was added to 900 ml of water for injection heated to 40 ° C. at a concentration shown in Table 1 to completely dissolve it. To the obtained solution was slowly added 5 g of oxaliplatin and stirred until a clear solution was obtained. While stirring the resulting solution, water for injection heated to 40 ° C. was added to final volume to 1000 ml. The resulting solution was sterile filtered with a sterilized 0.2 μm filter in a sterile chamber. The resulting solution was filled into a wash sterilized sealable container. The components and pH of the obtained oxaliplatin-containing solution are shown in Table 1 below.

Acetic acid concentration (M) Acetic acid addition amount (mg) Oxaliplatin carrier pH Concentration (mg / ml) Amount (g) Kinds Volume (ml) Example 1 0.0001 6.01 5 5 Water for injection 1000 5.71 Example 2 0.0004 24.04 5 5 Water for injection 1000 4.69 Example 3 0.001 60.10 5 5 Water for injection 1000 4.20 Example 4 0.005 300.50 5 5 Water for injection 1000 3.62

Example  2-9. Oxaliplatin Preparation of Solutions

To the composition and content of Table 2 below, an oxaliplatin-containing solution was prepared in the same manner as in Example 1.

Stabilizer Oxaliplatin carrier pH Kinds Concentration (m) Amount (mg) Concentration (mg / ml) Amount (g) Kinds Volume (ml) pH Example 5 Ammonium Citrate Oxalate 0.0001 0.001 19.21 142.10 5 5 Water for injection 1000 4.75 Example 6 Ammonium Citrate Oxalate 0.001 0.001 192.10 142.10 5 5 Water for injection 1000 3.47 Example 7 Ammonium Citrate Oxalate 0.001 0.0004 192.10 56.84 5 5 Water for injection 1000 3.66 Example 8 Ammonium Acetate Oxalate 0.001 0.001 60.10 142.10 5 5 Water for injection 1000 4.62 Example 9 Ammonium Acetate Oxalate 0.001 0.001 60.10 142.10 2 2 Water for injection 1000 4.75

Comparative example  1-4.

To the composition and content of Table 3 below, an oxaliplatin-containing solution 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, and Comparative Examples 2 to 3 are solutions prepared using ammonium oxalate as a stabilizer.

Stabilizer Oxaliplatin carrier pH Kinds Concentration (m) Amount (mg) Concentration (mg / ml) Amount (g) Kinds Volume (ml) Comparative Example 1 5 5 Water for injection 1000 5.50 Comparative Example 2 Ammonium oxalate 0.0001 14.21 5 5 Water for injection 1000 5.25 Comparative Example 3 Ammonium oxalate 0.0004 56.84 5 5 Water for injection 1000 5.70 Comparative Example 4 Ammonium oxalate 0.001 142.10 5 5 Water for injection 1000 5.78

Test Example  1. Stability Assessment (1)

The oxaliplatin-containing solution of Comparative Examples 1 to 4 was stored for 2 months under conditions of 25 ° C./60% relative humidity and 40 ° C./75% relative humidity, and then converted into B, B, C and C unknowns. The analog was analyzed by high performance liquid chromatography (HPLC) and the results are shown in Table 4.

Stabilizer pH Storage condition Leading substance B (%) Lead E (%) Leading substance C (%) Unknown flexible material (%) Kinds Concentration (m) Comparative Example 1 Water for injection 5.50 Early 0.3 0.4 0.1 0.1 25 ℃ / 60% RH 0.3 0.5 0.1 0.0 40 ℃ / 75% RH 0.3 0.6 0.1 0.0 Comparative Example 2 Ammonium oxalate 0.0001 5.25 Early 0.2 0.2 0.1 ND 25 ℃ / 60% RH 0.2 0.2 0.1 0.0 40 ℃ / 75% RH 0.3 0.2 0.1 0.1 Comparative Example 3 Ammonium oxalate 0.0004 5.70 Early 0.2 0.2 0.1 0.0 25 ℃ / 60% RH 0.3 0.3 0.1 0.0 40 ℃ / 75% RH 0.3 0.0 0.1 0.0 Comparative Example 4 Ammonium oxalate 0.001 5.78 Early 0.1 0.1 0.1 ND 25 ℃ / 60% RH 0.2 0.1 0.1 0.0 40 ℃ / 75% RH 0.3 ND 0.1 0.0

* ND: not detected.

As can be seen from the results in Table 4, in the case of the oxaliplatin-containing solution using only water for injection without using a stabilizer, impurities, for example, B and E, have greatly increased and the solution is very unstable. When ammonium oxalate is used as a stabilizer, generation of analog E in all concentration ranges is detected, indicating low stability.

Test Example  2. Evaluation of stability (2)

After storing the oxaliplatin-containing solution of Examples 1 to 8 for 2 months under conditions of 25 ° C./60% relative humidity, the flexible material B, the flexible material E, the flexible material C, and the unknown flexible material were subjected to high performance liquid chromatography ( HPLC), and the results are shown in Table 5.

Stabilizer pH Storage period Lead B (%) Lead E (%) Leading material C (%) Unknown flexible material (%) Kinds Concentration (m) Example 1 Acetic acid 0.0001 5.71 Early 0.3 ND 0.0 ND 2 months 0.4 ND 0.1 ND Example 2 Acetic acid 0.0004 4.74 Early 0.4 ND 0.0 0.0 2 months 0.4 ND 0.0 0.0 Example 3 Acetic acid 0.001 4.27 Early 0.4 ND 0.0 0.1 2 months 0.4 ND 0.0 0.0 Example 4 Acetic acid 0.005 3.65 Early 0.5 0.01 0.0 0.1 2 months 0.5 ND 0.0 0.0 Example 5 Citric Acid + Ammonium Oxalate 0.0001 0.001 4.75 Early 0.0 ND 0.1 0.1 2 months 0.0 ND 0.0 0.0 Example 6 Citric Acid + Ammonium Oxalate 0.001 0.001 3.47 Early 0.1 ND 0.0 0.1 2 months 0.1 ND 0.1 0.0 Example 7 Citric Acid + Ammonium Oxalate 0.001 0.0004 3.66 Early 0.2 ND 0.0 0.1 2 months 0.1 ND 0.1 ND Example 8 Acetic Acid + Ammonium Oxalate 0.001 0.001 4.62 Early 0.0 ND 0.0 ND 2 months 0.0 ND 0.0 ND

* ND: not detected.

As can be seen in Table 5, when the concentration of acetic acid is 0.005 M relative excess, the generation of lead material is FDA standard (flexible material B: 0.4% or less, lead material E: non-detection, lead material C: 0.1 % Or less, unknown lead: 0.2% or less). In contrast, when acetic acid concentration is 0.0001 to 0.001 M, or when citric acid and ammonium oxalate having a predetermined concentration, or acetic acid and ammonium oxalate are used as a stabilizer, it can be seen that the FDA meets the FDA standard.

Example  10-25. Oxaliplatin Preparation of Solutions

To the composition and content of Table 6 below, an oxaliplatin-containing solution was prepared in the same manner as in Example 1.

Stabilizer Oxaliplatin carrier Kinds Concentration (m) Amount (mg) Concentration (mg / ml) Amount (g) Kinds Volume (ml) Example 10 Ammonium Acetate Oxalate 0.0001 0.0001 6.01 14.21 5 5 Water for injection 1000 Example 11 Ammonium Acetate Oxalate 0.0001 0.0004 6.01 56.84 5 5 Water for injection 1000 Example 12 Ammonium Acetate Oxalate 0.0001 0.001 6.01 142.10 5 5 Water for injection 1000 Example 13 Ammonium Acetate Oxalate 0.0004 0.0001 24.04 14.21 5 5 Water for injection 1000 Example 14 Ammonium Acetate Oxalate 0.0004 0.0004 24.04 56.84 5 5 Water for injection 1000 Example 15 Ammonium Acetate Oxalate 0.0004 0.001M 24.04 142.10 2 2 Water for injection 1000 Example 16 Ammonium Citrate Oxalate 0.0001 0.0001 19.21 14.21 5 5 Water for injection 1000 Example 17 Ammonium Citrate Oxalate 0.0001 0.0004 19.21 56.84 5 5 Water for injection 1000 Example 18 Ammonium Citrate Oxalate 0.0004 0.0001 76.84 14.21 5 5 Water for injection 1000 Example 19 Ammonium Citrate Oxalate 0.0004 0.0004 76.84 56.84 5 5 Water for injection 1000 Example 20 Ammonium Citrate Oxalate 0.0004 0.001 76.84 142.10 5 5 Water for injection 1000 Example 21 Ammonium Citrate Oxalate 0.001 0.0001 192.10 14.21 5 5 Water for injection 1000 Example 22 Ammonium Citrate Oxalate 0.0001 0.0001 19.21 14.21 One One Water for injection 1000 Example 23 Ammonium Citrate Oxalate 0.0001 0.0001 19.21 14.21 7 7 Water for injection 1000 Example 24 Ammonium Citrate Oxalate 0.00001 0.00001 1.92 1.42 5 5 Water for injection 1000 Example 25 Ammonium Citrate Oxalate 0.01 0.01 1921 1421 5 5 Water for injection 1000

Claims (5)

1 × 10 ⁻⁴ M to 1 × 10 ⁻³ M acetic acid as stabilizer; Oxaliplatin; And an pharmaceutically acceptable carrier. An oxaliplatin-containing injectable solution. delete delete delete The oxaliplatin-containing solution for injection according to claim 1, wherein the oxaliplatin content is 1 to 7 mg / ml.