Stable aqueous solution of oxaliplatin and method for its preparation and use

Abstract

The application discloses a stable oxaliplatin aqueous solution and belongs to the technical field of medicines. The application provides a stable oxaliplatin aqueous solution, a preparation method and application thereof, which contains citric acid and sodium citrate in a molar ratio of (0.6:1.4) to (0.8:1.2), the molar concentration of the citric acid in the aqueous solution is 3*10 ‑4 ~4*10 ‑4 M, the molar concentration of the sodium citrate is 6*10 ‑4 ~7*10 ‑4 M, and the mass concentration of the oxaliplatin is 2-6 mg / ml. Compared with the prior art, the oxaliplatin aqueous solution has better stability, lower impurity content, and no impurity C is detected; the pH value is stable before and after sterilization, the pH value range is 5.0-5.5, is closer to the pH of human body fluid, has less irritancy, and has higher safety.

Description

Technical Field

[0001] This invention relates to a stable aqueous solution of oxaliplatin, its preparation method, and its uses, belonging to the field of pharmaceutical technology. Background Technology

[0002] Oxaliplatin (L-OHP), also known as oxaliplatin or oxalate platinum, has the chemical formula C8H. 12 N₂O₄Pt, with a molecular weight of 395.28, is chemically named (1R-trans)-(1,2-cyclohexanediamine-N,N')[oxalate (Z-)-O,O']platinum. Oxaliplatin is clinically used to treat patients with metastatic colorectal cancer who have failed fluorouracil therapy. It can be used alone or in combination with fluorouracil. It is a third-generation platinum-based antitumor compound after cisplatin and carboplatin, and is the only platinum-based drug to date with significant activity against colorectal cancer. Oxaliplatin's chemical structure differs significantly from cisplatin and carboplatin. This drug not only improves the toxic side effects of cisplatin and carboplatin but also broadens their activity spectrum, exhibiting activity against some cisplatin- or carboplatin-resistant tumors. It has better efficacy, lower toxicity, and no cross-resistance with cisplatin and carboplatin. Its structural formula is:

[0003]

[0004] Currently, oxaliplatin is available in both lyophilized and injectable formulations. However, the application of lyophilized formulations is limited due to significant drawbacks. Firstly, lyophilized formulations utilize a sterile filtration process, which, compared to terminal sterilization, results in a lower level of sterility assurance and a greater risk of sterilization failure. Secondly, lyophilized formulations require reconstitution before clinical use, leading to cumbersome procedures, a high risk of contamination, and potential issues such as instability and incomplete powder dissolution after reconstitution. Furthermore, the addition of animal-derived lactose to lyophilized formulations may introduce contaminating proteins such as α-S1 casein and β-lactoglobulin, increasing the risk of allergic reactions during clinical use.

[0005] Given the aforementioned drawbacks of lyophilized oxaliplatin formulations, efforts have been made to develop a stable, readily available aqueous liquid formulation of oxaliplatin. However, due to the presence of a weak oxalic acid anion and a central platinum atom in its structure, oxaliplatin is unstable in aqueous solution and readily generates the following hydrolytic and oxidative impurities: impurity A (oxalic acid), impurity B (cyclohexanediamine dihydrate platinum), impurity C (dihydroxyoxaliplatin), and impurity E (cyclohexanediamine dihydrate platinum dimer). The structures of these impurities are as follows:

[0006]

[0007] Impurities A, B, and E are produced by the hydrolysis of oxaliplatin. The hydrolysis reaction mainly involves two steps: first, oxaliplatin hydrolyzes to produce oxalic acid (impurity A); then, the five-membered ring of oxalic acid opens to form a monodentate oxalic acid complex, which then completely dissociates to form cyclohexanediamine dihydrate platinum (impurity B). The chemical reaction pathways of these two steps differ under different pH conditions. Cyclohexanediamine dihydrate platinum can further polymerize to form a cyclohexanediamine dihydrate platinum dimer (impurity E).

[0008] Impurity C is an impurity generated by the oxidation of oxaliplatin, and its reaction process is as follows:

[0009]

[0010] The presence of these impurities poses challenges to the efficacy and safety of oxaliplatin liquid formulations in clinical use. Therefore, improving the stability of the formulation and reducing the content of these impurities is crucial when preparing aqueous oxaliplatin liquid formulations. However, due to the poor stability of oxaliplatin in aqueous solutions, it is currently difficult to effectively reduce the content of related substances in aqueous liquid formulations. The United States Pharmacopeia (USP) 41 stipulates that impurity A in oxaliplatin injection should not exceed 0.6%, impurity B should not exceed 0.65%, impurity E should not exceed 0.5%, other individual impurities should not exceed 0.2%, and total impurities should not exceed 2.45%. However, these limits are still relatively high, which is detrimental to ensuring the efficacy and safety of the drug. There is a need in the field to further reduce the impurity content.

[0011] Chinese patent application CN 102274171A discloses an oxaliplatin injection, which is composed of oxaliplatin, a buffer solution formed by acetic acid and sodium acetate, and water for injection. According to the patent text, to control the impurity content at a relatively low level using its formulation and preparation process, the pH of the solution needs to be controlled between 3.7 and 4.7. However, the solution is acidic within this pH range, which can cause some irritation during clinical use. If the pH of the preparation is adjusted to other ranges, the content of impurities A and B will be too high (see the related substance detection data of preparations 10 and 11 in paragraph

[0058] of the CN 102274171A specification), resulting in poor stability.

[0012] WO 9943355 discloses an oxaliplatin solution formulation consisting of oxaliplatin, oxalic acid, or an alkali metal salt thereof as a buffer, and a pharmaceutically acceptable carrier. Because oxalic acid itself is toxic and can damage the kidneys and other organs, the use of this formulation in pharmaceutical products is limited. Summary of the Invention

[0013] This invention aims to at least solve one of the technical problems existing in the prior art. Therefore, an object of this invention is to provide a stable aqueous solution of oxaliplatin. A second object of this invention is to provide an aqueous solution of oxaliplatin with lower impurity content. Another object of this invention is to provide a method for preparing the said aqueous solution of oxaliplatin and its uses.

[0014] This invention provides a stable oxaliplatin aqueous solution containing citric acid and sodium citrate in a molar ratio of (0.6:1.4) to (0.8:1.2), wherein the molar concentration of citric acid in the aqueous solution is 3 × 10⁻⁶. -4 ~4×10 -4 M, the molar concentration of sodium citrate is 6 × 10⁻⁶. -4 ~7×10 -4 M, the mass concentration of oxaliplatin is 2-6 mg / ml.

[0015] This invention has found that the ratio and concentration of citric acid and sodium citrate have a significant effect on the impurity content of oxaliplatin aqueous solution. Within the above molar ratio and concentration range, the impurity content of oxaliplatin aqueous solution can be effectively reduced.

[0016] Furthermore, the molar ratio of citric acid to sodium citrate is 0.7:1.3. At this molar ratio, the oxaliplatin aqueous solution exhibits the lowest impurity content.

[0017] Furthermore, the molar concentration of citric acid in the aqueous solution is 3.3 × 10⁻⁶. -4 ~3.7×10 -4 M, the molar concentration of sodium citrate is 6.3 × 10⁻⁶. -4 ~6.7×10 -4 M.

[0018] Preferably, the molar concentration of citric acid in the aqueous solution is 3.5 × 10⁻⁶. -4 M, the molar concentration of sodium citrate is 6.5 × 10⁻⁶. -4 M. At the above molar concentrations, the oxaliplatin aqueous solution has the lowest impurity content.

[0019] Furthermore, the mass concentration of oxaliplatin is 5 mg / ml.

[0020] Furthermore, the pH value of the aqueous solution is 5.0–5.5. The oxaliplatin aqueous solution of this invention has a pH value closer to that of human bodily fluids, resulting in less irritation and higher safety when used on the human body, thus exhibiting better product quality.

[0021] Preferably, the pH value of the aqueous solution is 5.2 to 5.4.

[0022] More preferably, the pH value of the aqueous solution is 5.3.

[0023] Furthermore, the aqueous solution is composed of oxaliplatin, citric acid, sodium citrate, and water as a solvent.

[0024] The present invention also provides an aqueous solution of oxaliplatin, wherein the oxaliplatin solution is free of impurity C.

[0025] Furthermore, the oxaliplatin aqueous solution also satisfies at least one of the following: based on the labeled amount of oxaliplatin, the content of impurity A is ≤0.18%; the content of impurity B is ≤0.12%; the content of impurity E is ≤0.16%; and the total impurity content is ≤0.42%.

[0026] Preferably, the composition of the oxaliplatin aqueous solution is as defined in any of the preceding claims.

[0027] The present invention also provides a method for preparing the oxaliplatin aqueous solution, which includes the following steps: dissolving oxaliplatin in water, adding citric acid and sodium citrate, and mixing evenly.

[0028] Compared with lyophilized formulations, the preparation method of the oxaliplatin aqueous solution of the present invention is simple to operate, has a lower cost, a higher level of sterility assurance, and is more convenient for clinical use.

[0029] Preferably, citric acid and sodium citrate are added in the form of an aqueous solution.

[0030] Preferably, the preparation method further includes the following step: purging the prepared oxaliplatin aqueous solution with nitrogen until the dissolved oxygen content is below 0.2 mg / L.

[0031] Preferably, the preparation method further includes a filling step, and after filling, nitrogen is purged until the headspace oxygen is ≤3%.

[0032] The present invention also provides the use of the oxaliplatin aqueous solution in the preparation of liquid pharmaceutical formulations.

[0033] Preferably, the liquid pharmaceutical preparation is an injection solution.

[0034] Finally, this invention provides the use of the oxaliplatin aqueous solution in the preparation of medicaments for treating cancer.

[0035] This invention provides a stable aqueous solution of oxaliplatin, its preparation method, and its uses, and has at least the following beneficial technical effects:

[0036] 1. Compared with the prior art, the oxaliplatin aqueous solution of the present invention has better stability, lower impurity content, and no impurity C was detected.

[0037] 2. Compared with currently known oxaliplatin solution compositions, the present invention has a pH that is closer to that of human body fluids, resulting in less irritation and higher safety when used on the human body.

[0038] 3. Compared with lyophilized formulations, the preparation method of oxaliplatin aqueous solution of the present invention is simple to operate, has a lower cost, a higher level of sterility assurance, and is more convenient for clinical use. Detailed Implementation

[0039] The present invention will be further illustrated below through specific embodiments and experiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0040] Example 1: Preparation of Formulation 1

[0041] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of citrate-sodium citrate buffer solution, wherein the molar ratio of citrate to sodium citrate in the buffer solution is 0.7:1.3, and the molar concentrations of citrate and sodium citrate are 0.035M and 0.065M, respectively; then add water for injection to a final volume of 1000ml; purge with nitrogen until dissolved oxygen is below 0.2mg / L, filter, fill (purge with nitrogen until headspace oxygen is below 3%), stopper, crimp cap, and finally sterilize at 121℃ for 15 minutes. The resulting oxaliplatin solution composition is designated as Formulation 1.

[0042] Example 2: Preparation of Formulation 2

[0043] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of citrate-sodium citrate buffer solution, wherein the molar ratio of citrate to sodium citrate in the buffer solution is 0.6:1.4, and the molar concentrations of citrate and sodium citrate are 0.03M and 0.07M, respectively; then add water for injection to a final volume of 1000ml; purge with nitrogen until dissolved oxygen is below 0.2mg / L, filter, fill (purge with nitrogen until headspace oxygen is below 3%), stopper, and cap, and finally sterilize by moist heat at 121℃ for 15 minutes. The resulting oxaliplatin solution composition is designated as formulation 2.

[0044] Example 3: Preparation of Formulation 3

[0045] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of citrate-sodium citrate buffer solution, wherein the molar ratio of citrate to sodium citrate in the buffer solution is 0.8:1.2, and the molar concentrations of citrate and sodium citrate are 0.04M and 0.06M, respectively; then add water for injection to a final volume of 1000ml; purge with nitrogen until dissolved oxygen is below 0.2mg / L, filter, fill (purge with nitrogen until headspace oxygen is below 3%), stopper, and cap, and finally sterilize by moist heat at 121℃ for 15 minutes. The resulting oxaliplatin solution composition is designated as formulation 3.

[0046] Preparation of Formulation 4 in Comparative Example 1

[0047] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of acetate-sodium acetate buffer solution, wherein the molar ratio of acetic acid to sodium acetate in the buffer solution is 4:1, and the molar concentrations of acetate and sodium acetate are 0.2M and 0.05M, respectively; then add water for injection to a final volume of 1000ml; filter, fill, stopper, and cap, and finally sterilize at 121℃ for 15 minutes by moist heat. The resulting oxaliplatin solution composition is designated as formulation 4.

[0048] Preparation of Formulation 5 in Comparative Example 2

[0049] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of 0.02M oxalic acid aqueous solution; then add water for injection to make up to 1000ml; filter, fill, stopper, and cap, and finally sterilize at 121℃ for 15 minutes by moist heat. The resulting oxaliplatin solution composition is designated as formulation 5.

[0050] Preparation of Formulation 6 in Comparative Example 3

[0051] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of citrate-sodium citrate buffer solution, wherein the molar ratio of citrate to sodium citrate in the buffer solution is 0.5:1.5, and the molar concentrations of citrate and sodium citrate are 0.025M and 0.075M, respectively; then add water for injection to a final volume of 1000ml; purge with nitrogen until dissolved oxygen is below 0.2mg / L, filter, fill (purge with nitrogen until headspace oxygen is below 3%), stopper, crimp cap, and finally sterilize by moist heat at 121℃ for 15 minutes. The resulting oxaliplatin solution composition is designated as formulation 6.

[0052] Preparation of Formulation 7 in Comparative Example 4

[0053] Accurately weigh 5g of oxaliplatin into a container, then add 900ml of water for injection at 50℃, stir until oxaliplatin is completely dissolved, and cool to room temperature; add 10ml of citrate-sodium citrate buffer solution, wherein the molar ratio of citrate to sodium citrate in the buffer solution is 1:1, and the molar concentrations of citrate and sodium citrate are 0.05M and 0.05M, respectively; then add water for injection to a final volume of 1000ml; purge with nitrogen until dissolved oxygen is below 0.2mg / L, filter, fill (purge with nitrogen until headspace oxygen is below 3%), stopper, and cap, and finally sterilize by moist heat at 121℃ for 15 minutes. The resulting oxaliplatin solution composition is designated as formulation 7.

[0054] Verification Experiment Example

[0055] I. Examination of formulation content, pH and related substances

[0056] The contents, pH, and contents of related substances of formulations 1-7 and the commercially available original formulation (manufactured by Sanofi-Aventis South Africa, 10ml:50mg, composed of oxaliplatin and water) were tested according to the test items for oxaliplatin injection in USP 41. The content of oxidizing impurity C was added to the USP 41 test items. Related substances tested included impurity A (oxalic acid), impurity B (cyclohexanediamine dihydrate platinum), impurity C (dihydroxyoxaliplatin), impurity E (cyclohexanediamine dihydrate platinum dimer), unknown single impurities, and total impurities. The test results are shown in Table 1.

[0057] Table 1. Results of tests on formulation content, pH, and related substances content.

[0058]

[0059]

[0060] The test results show that, compared with the original injectable solution, the content of impurities A, B, C, E, single impurities, and total impurities in the oxaliplatin solution composition of the present invention is reduced, especially since the present invention avoids the formation of impurity C; compared with existing injectable products using acetic acid and sodium acetate as buffer solutions (formulation 4), the content of impurities B, C, single impurities, and total impurities in the formulation of the present invention is lower; compared with existing injectable products containing oxalic acid (formulation 5), the content of impurities A, C, single impurities, and total impurities in the formulation of the present invention is lower.

[0061] Comparing formulations 1-3 with formulations 6 and 7, it can be seen that the ratio and concentration of citric acid and sodium citrate have a significant impact on the impurity content of the oxaliplatin solution composition. In formulation 6, the molar ratio of citric acid to sodium citrate is 0.5:1.5, and the molar concentrations of citric acid and sodium citrate are 0.025M and 0.075M, respectively. As a result, the contents of impurity B, impurity E, and total impurities are increased. In formulation 7, the molar ratio of citric acid to sodium citrate is 1:1, and the molar concentrations of citric acid and sodium citrate are 0.05M and 0.05M, respectively. As a result, the contents of impurity A, impurity B, single impurities, and total impurities are increased.

[0062] Based on the above experimental results, the oxaliplatin solution composition provided by this invention has better quality than the currently known oxaliplatin injections, mainly reflected in the following aspects: the product of this invention has the lowest impurity content, stable pH value before and after sterilization, and a pH value range of 5.0 to 5.5, and less irritation.

[0063] II. Stability Test

[0064] The effects of high temperature (60℃) on formulations 1, 4, and 5 were tested. After being placed at 60℃ for 30 days, their content, pH value, and amount of related substances were measured. The results are shown in Table 2.

[0065] Table 2. Stability test results

[0066]

[0067]

[0068] The stability study results show that, compared with the acetate-sodium acetate or oxalic acid-water buffer solutions used in the prior art, the present invention uses citrate-sodium citrate as a buffer solution, which improves the stability of oxaliplatin liquid drug formulation and effectively reduces the content of related substances.

Claims

1. A stable aqueous solution of oxaliplatin, characterized in that: containing citric acid and sodium citrate in a molar ratio of 0.7:1.3, the molar concentration of citric acid in the aqueous solution being 3.5 x 10 -4 M, the molar concentration of sodium citrate being 6.5 x 10 -4 M; the mass concentration of oxaliplatin being 5 mg / ml; the pH of the aqueous solution being 5.3; The oxaliplatin aqueous solution does not contain impurity C; The oxaliplatin aqueous solution further satisfies at least one of the following: the content of impurity A is ≤0.18% based on the labeled amount of oxaliplatin; the content of impurity B is ≤0.12%; the content of impurity E is ≤0.16%; the total content of impurities is ≤0.42%; The impurity A is oxalic acid; The impurity B is cyclohexanediamine platinum dihydrate; The impurity C is bis-hydroxyl oxaliplatin; The impurity E is cyclohexanediamine platinum dihydrate dimer.

2. The method of claim 1, wherein the aqueous solution of oxaliplatin is prepared by: The method comprises the following steps: dissolving oxaliplatin in water, adding citric acid and sodium citrate, and mixing uniformly.

3. The method of claim 2, wherein the aqueous solution of oxaliplatin is prepared by the steps of: The citric acid and the sodium citrate are added in the form of an aqueous solution.

4. The method of claim 3 wherein: The preparation method further comprises the following step: filling nitrogen into the prepared oxaliplatin aqueous solution to a dissolved oxygen content of ≤0.2 mg / L.

5. The method of claim 4 wherein: The preparation method further comprises a filling step, and after filling, nitrogen is filled to a headspace oxygen content of ≤3%.

6. Use of the oxaliplatin aqueous solution of claim 1 in the preparation of a liquid pharmaceutical preparation.

7. Use according to claim 6, characterized in that, The liquid pharmaceutical preparation is an injection.

8. Use of the oxaliplatin aqueous solution of claim 1 in the preparation of a drug for treating cancer.

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