CN116139079A - Stable oxaliplatin aqueous solution, preparation method and application thereof - Google Patents
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Abstract
The invention discloses a stable oxaliplatin aqueous solution, and belongs to the technical field of medicines. The invention provides a stable oxaliplatin aqueous solution, a preparation method and application thereof, and the stable oxaliplatin aqueous solution comprises citric acid with the molar ratio of (0.6:1.4) to (0.8:1.2): sodium citrate, the molar concentration of citric acid in the aqueous solution is 3×10 ‑4 ～4×10 ‑4 M, molar concentration of sodium citrate is 6×10 ‑4 ～7×10 ‑4 M, oxaliplatin mass concentration is 2-6 mg/ml. Compared with the prior art, the oxaliplatin aqueous solution has better stability, lower impurity content and no detected impurity C; the pH value before and after sterilization is stable, and the pH value range is 5.0-5.5, which is more similar to the human bodyThe pH of the body fluid is less in irritation and higher in safety.
Description
Technical Field
The invention relates to a stable oxaliplatin aqueous solution, a preparation method and application thereof, belonging to the technical field of medicines.
Background
Oxaliplatin (L-OHP), also known as Lexadine, platinum oxalate, with chemical formula C 8 H 12 N 2 O 4 Pt, molecular weight 395.28, chemical name (1R-trans) - (1, 2-cyclohexanediamine-N, N ') [ oxalic acid (Z-) -O, O ]']And (3) platinum synthesis. Oxaliplatin is clinically used for treating patients with colorectal cancer metastasis after failure of fluorouracil treatment, can be used singly or in combination with fluorouracil, is a third-generation novel platinum anti-tumor compound after cisplatin and carboplatin, and is the only platinum-complex drug with remarkable activity on colorectal cancer so far. The chemical structure of oxaliplatin has obvious difference with that of cisplatin and carboplatin, and the medicine not only can better improve the toxic and side effects of cisplatin and carboplatin, but also can enlarge the activity spectrum of cisplatin and carboplatin, and has better curative effect and lower toxicity on some cisplatin-or carboplatin-resistant tumors, and has no cross drug resistance with cisplatin and carboplatin. The structural formula is as follows:
currently, oxaliplatin is marketed in lyophilized formulations and injection solutions, wherein the use of the lyophilized formulations is limited due to the obvious drawbacks. Firstly, the freeze-dried preparation adopts a production process of sterilization filtration, and compared with terminal sterilization, the sterilization filtration can ensure the sterility assurance level of the preparation to be relatively lower, and has larger risk of sterilization failure. Furthermore, the freeze-dried preparation needs to be re-dissolved in clinical use, thereby bringing the defects of complex operation and high risk of bacteria infection, and the problems of unstable preparation, insufficient powder dissolution and the like after re-dissolution can also occur. Furthermore, the addition of animal derived lactose to the lyophilized formulation may increase the risk of clinical allergy in use due to the presence of miscellaneous proteins such as alpha-S1 casein and beta-lactoglobulin.
In view of the above-described drawbacks of lyophilized formulations of oxaliplatin, efforts have been directed to developing a stable, ready-to-use aqueous liquid formulation of oxaliplatin. However, oxaliplatin structure contains oxalate weak acid radical and central platinum atom, which makes it unstable in aqueous solution, and the following hydrolysis and oxidation impurities are easy to generate: impurity a (oxalic acid), impurity B (cyclohexanediamine platinum dihydrate), impurity C (bishydroxy oxaliplatin), impurity E (cyclohexanediamine platinum dimer dihydrate). The structures of these impurities are respectively:
the impurity A, the impurity B and the impurity E are impurities generated by the hydrolysis of oxaliplatin, and the hydrolysis reaction mainly comprises two steps: first oxaliplatin hydrolyzes to oxalic acid (impurity a), then the five-membered ring of oxalic acid opens to form an oxalic acid monodentate complex, followed by complete dissociation to form cyclohexanediamine platinum dihydrate (impurity B), the two chemical reactions being different in the manner of different pH conditions. The cyclohexanediamine platinum dihydrate can further polymerize to form cyclohexanediamine platinum dihydrate dimer (impurity E).
The impurity C is an impurity generated by oxidation of oxaliplatin, and the reaction process is as follows:
the presence of the above impurities will bring problems of effectiveness and safety to clinical administration of oxaliplatin liquid pharmaceutical formulations, so that it is important to improve the stability of the formulations and reduce the content of these impurities when preparing oxaliplatin aqueous liquid formulations. However, it is currently difficult to effectively reduce the content of the relevant substances in aqueous liquid formulations due to poor stability of oxaliplatin in aqueous solutions. The USP41 specifies that the oxaliplatin injection must not exceed 0.6% of impurity a, must not exceed 0.65% of impurity B, must not exceed 0.5% of impurity E, must not exceed 0.2% of other single impurities and must not exceed 2.45% of total impurities, but the impurity limit is still high, which is not beneficial to ensuring the effectiveness and safety of the drug, and there is a need in the art to further reduce the impurity content.
Chinese patent application CN 102274171a discloses an oxaliplatin injection, which consists of oxaliplatin, a buffer solution formed by acetic acid and sodium acetate, and water for injection. According to the patent document, the prescription type and the preparation process are adopted, and in order to control the impurity content to be at a relatively low level, the pH of the solution needs to be controlled to be 3.7-4.7, but the liquid medicine is slightly acidic in the pH range, and certain irritation is brought to clinical use; if the pH of the preparation is adjusted to other ranges, the contents of the impurity A and the impurity B are both high (see detection data of substances related to the preparations 10 and 11 in the paragraph [0058] of the specification CN 102274171A), and the stability is poor.
WO 9943355 discloses an oxaliplatin solution formulation consisting of a buffer for oxaliplatin, oxalic acid or an alkali metal salt thereof and a pharmaceutically acceptable carrier. Oxalic acid itself is toxic and can damage kidneys and other organs, resulting in limited use of the formulation in pharmaceutical products.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention aims to provide a stable aqueous oxaliplatin solution. A second object of the present invention is to provide an aqueous oxaliplatin solution having a lower impurity content. Another object of the present invention is to provide a process for the preparation and use of said aqueous oxaliplatin solution.
The invention provides a stable oxaliplatin aqueous solution, which contains citric acid with the molar ratio of (0.6:1.4) to (0.8:1.2): sodium citrate, the molar concentration of citric acid in the aqueous solution is 3×10 -4 ～4×10 -4 M, molar concentration of sodium citrate is 6×10 -4 ～7×10 -4 M, oxaliplatin mass concentration is 2-6 mg/ml.
The invention discovers that the proportion and the concentration of the added citric acid and sodium citrate have obvious influence on the impurity content of the oxaliplatin aqueous solution, and the impurity content of the oxaliplatin aqueous solution can be effectively reduced within the molar proportion and the concentration range.
Further, the molar ratio of citric acid to sodium citrate is 0.7:1.3. At the above molar ratio, the oxaliplatin aqueous solution has the lowest impurity content.
Further, the molar concentration of citric acid in the aqueous solution is 3.3X10 -4 ～3.7×10 -4 M, molar concentration of sodium citrate is 6.3X10 -4 ～6.7×10 -4 M。
Preferably, the molar concentration of citric acid in the aqueous solution is 3.5X10 -4 M, molar concentration of sodium citrate is 6.5X10 -4 M. At the above molar concentrations, the oxaliplatin aqueous solution has the lowest impurity content.
Further, the mass concentration of oxaliplatin is 5mg/ml.
Further, the pH value of the aqueous solution is 5.0-5.5. The oxaliplatin aqueous solution has the pH value closer to that of human body fluid, so that the oxaliplatin aqueous solution has smaller irritation and higher safety when being used by a human body, and has better product quality.
Preferably, the pH of the aqueous solution is between 5.2 and 5.4.
Further preferably, the pH of the aqueous solution is 5.3.
Further, the aqueous solution is composed of oxaliplatin, citric acid, sodium citrate and solvent water.
The invention also provides an oxaliplatin aqueous solution, which does not contain impurity C.
Further, the aqueous oxaliplatin solution further satisfies at least one of the following: the content of the impurity A is less than or equal to 0.18 percent based on the marked amount of oxaliplatin; the content of the impurity B is less than or equal to 0.12 percent; the content of the impurity E is less than or equal to 0.16%; the total impurity content is less than or equal to 0.42 percent.
Preferably, the composition of the aqueous oxaliplatin solution is as defined in any one of the preceding claims.
The invention also provides a preparation method of the oxaliplatin aqueous solution, which comprises the following steps: dissolving oxaliplatin in water, adding citric acid and sodium citrate, and mixing.
Compared with a freeze-dried preparation, the preparation method of the oxaliplatin aqueous solution has the advantages of simple operation, lower cost, high sterility assurance level and more convenience in clinical use.
Preferably, citric acid and sodium citrate are added as aqueous solutions.
Preferably, the preparation method further comprises the following steps: and (3) charging nitrogen into the prepared oxaliplatin aqueous solution until the dissolved oxygen content is below 0.2 mg/L.
Preferably, the preparation method further comprises a filling step, and nitrogen is filled after filling until the oxygen content in the headspace is less than or equal to 3%.
The invention also provides application of the oxaliplatin aqueous solution in preparing a liquid pharmaceutical preparation.
Preferably, the liquid pharmaceutical formulation is an injection.
The invention finally provides the use of said aqueous oxaliplatin solution for the manufacture of a medicament for the treatment of cancer.
The invention provides a stable oxaliplatin aqueous solution, a preparation method and application thereof, and has at least the following beneficial technical effects:
1. compared with the prior art, the oxaliplatin aqueous solution has better stability, lower impurity content and no detected impurity C.
2. Compared with the prior known oxaliplatin solution composition, the invention has the pH value closer to that of human body fluid, so that the oxaliplatin solution composition has smaller irritation and higher safety when being used by human body.
3. Compared with a freeze-dried preparation, the preparation method of the oxaliplatin aqueous solution has the advantages of simple operation, lower cost, high sterility assurance level and more convenience in clinical use.
Detailed Description
The following will further illustrate the embodiments of the present invention by way of specific embodiments and experiments. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 preparation of formulation 1
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of a citric acid-sodium citrate buffer solution was added, wherein: the molar ratio of the citric acid to the sodium citrate in the buffer solution is 0.7:1.3, and the molar concentrations of the citric acid and the sodium citrate are 0.035M and 0.065M respectively; then supplementing 1000ml with water for injection; filling nitrogen to less than 0.2mg/L of dissolved oxygen, filtering, filling (filling nitrogen to less than 3% of headspace oxygen), plugging, rolling a cover, and finally sterilizing at 121 ℃ for 15 minutes by wet heat, wherein the obtained oxaliplatin solution composition is denoted as a preparation 1.
Example 2 preparation of formulation 2
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of a citric acid-sodium citrate buffer solution was added, wherein: the molar ratio of the citric acid to the sodium citrate in the buffer solution is 0.6:1.4, and the molar concentration of the citric acid to the sodium citrate is 0.03M and 0.07M respectively; then supplementing 1000ml with water for injection; filling nitrogen to less than 0.2mg/L of dissolved oxygen, filtering, filling (filling nitrogen to less than 3% of headspace oxygen), plugging, rolling a cover, and finally sterilizing at 121 ℃ for 15 minutes by wet heat, wherein the obtained oxaliplatin solution composition is denoted as preparation 2.
Example 3 preparation of formulation 3
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of a citric acid-sodium citrate buffer solution was added, wherein: the molar ratio of the citric acid to the sodium citrate in the buffer solution is 0.8:1.2, and the molar concentration of the citric acid to the sodium citrate is 0.04M and 0.06M respectively; then supplementing 1000ml with water for injection; filling nitrogen to less than 0.2mg/L of dissolved oxygen, filtering, filling (filling nitrogen to less than 3% of headspace oxygen), plugging, rolling a cover, and finally sterilizing at 121 ℃ for 15 minutes by wet heat, wherein the obtained oxaliplatin solution composition is denoted as preparation 3.
Comparative example 1 preparation of formulation 4
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of acetic acid-sodium acetate buffer solution was added, wherein: the molar ratio of acetic acid to sodium acetate in the buffer solution is 4:1, and the molar concentration of acetic acid-sodium acetate is 0.2M and 0.05M respectively; then supplementing 1000ml with water for injection; filtering, filling, plugging, capping, and finally sterilizing at 121 ℃ for 15 minutes under damp heat, the solution composition of oxaliplatin is designated as formulation 4.
Comparative example 2 preparation of formulation 5
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of an aqueous oxalic acid solution with a molar concentration of 0.02M are added; then supplementing 1000ml with water for injection; filtering, filling, plugging, capping, and finally sterilizing at 121 ℃ for 15 minutes under damp heat, wherein the prepared oxaliplatin solution composition is denoted as preparation 5.
Comparative example 3 preparation of formulation 6
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of a citric acid-sodium citrate buffer solution was added, wherein: the molar ratio of the citric acid to the sodium citrate in the buffer solution is 0.5:1.5, and the molar concentration of the citric acid to the sodium citrate is 0.025M and 0.075M respectively; then supplementing 1000ml with water for injection; filling nitrogen to less than 0.2mg/L of dissolved oxygen, filtering, filling (filling nitrogen to less than 3% of headspace oxygen), plugging, rolling a cover, and finally performing wet heat sterilization at 121 ℃ for 15 minutes, wherein the prepared oxaliplatin solution composition is denoted as preparation 6.
Comparative example 4 preparation of formulation 7
Precisely weighing 5g of oxaliplatin into a container, adding 900ml of water for injection at 50 ℃, stirring until oxaliplatin is completely dissolved, and cooling to room temperature; 10ml of a citric acid-sodium citrate buffer solution was added, wherein: the molar ratio of the citric acid to the sodium citrate in the buffer solution is 1:1, and the molar concentration of the citric acid to the sodium citrate is 0.05M and 0.05M respectively; then supplementing 1000ml with water for injection; filling nitrogen to less than 0.2mg/L of dissolved oxygen, filtering, filling (filling nitrogen to less than 3% of headspace oxygen), plugging, rolling a cover, and finally sterilizing at 121 ℃ for 15 minutes by wet heat, wherein the obtained oxaliplatin solution composition is denoted as preparation 7.
Verification test example
1. Examination of formulation content, pH and related substances
Formulations 1 to 7 and commercially available raw preparation (manufactured by Sanofion Van. Co., ltd., specification: 10 ml: 50mg, composition of injection: oxaliplatin and water) were tested with reference to the test item contents of United states pharmacopoeia USP41 regarding oxaliplatin injection, pH and contents of related substances, and the test of oxidized impurity C content was increased on the basis of the USP41 test item. The substances of interest to be detected include impurity a (oxalic acid), impurity B (cyclohexanediamine platinum dihydrate), impurity C (dihydroxyoxaliplatin), impurity E (cyclohexanediamine platinum dimer dihydrate), unknown mono-and total impurities. The detection results are shown in Table 1.
TABLE 1 examination results of the formulation content, pH and related substance content
Compared with the original injection, the oxaliplatin solution composition has the advantages that the contents of impurities A, B, C, E, single impurities and total impurities are reduced, and particularly, the generation of the impurity C is avoided; compared with the existing injection product (preparation 4) which adopts acetic acid and sodium acetate as buffer solutions, the preparation has lower impurity B, impurity C, single impurity and total impurity content; the present formulation has lower levels of impurity a, impurity C, mono-and total impurities than the prior injection product (formulation 5) with oxalic acid added.
Comparing preparations 1 to 3 with preparations 6 and 7, it can be seen that the ratio and concentration of citric acid and sodium citrate have a significant effect on the impurity content of the oxaliplatin solution composition. Citric acid in formulation 6: the molar ratio of sodium citrate is 0.5:1.5, the molar concentration of citric acid and sodium citrate is 0.025M and 0.075M respectively, and as a result, the content of impurity B, impurity E and total impurities are increased; citric acid in formulation 7: the molar ratio of sodium citrate is 1:1, the molar concentrations of citric acid and sodium citrate were 0.05M and 0.05M, respectively, with the result that the contents of impurity A, impurity B, single impurity and total impurity were increased.
Based on the experimental results, the oxaliplatin solution composition provided by the invention has better quality compared with the prior known oxaliplatin injection, and is mainly characterized in that: the product of the invention has the advantages of minimum impurity content, stable pH value before and after sterilization, pH value range of 5.0-5.5 and smaller irritation.
2. Stability investigation
The formulations 1, 4 and 5 were subjected to high temperature 60℃influence factor test, and after being left at high temperature 60℃for 30 days, the contents, pH values and amounts of the related substances were measured, and the measurement results are shown in Table 2.
Table 2 stability investigation results
As can be seen from the stability inspection results, compared with acetic acid-sodium acetate or oxalic acid-water buffer solution adopted in the prior art, the invention adopts citric acid-sodium citrate as the buffer solution, improves the stability of oxaliplatin liquid pharmaceutical preparation, and effectively reduces the content of related substances.
Claims (10)
1. A stable aqueous oxaliplatin solution characterized by: contains citric acid with the molar ratio of (0.6:1.4) to (0.8:1.2): sodium citrate, the molar concentration of citric acid in the aqueous solution is 3×10 -4 ～4×10 -4 M, molar concentration of sodium citrate is 6×10 -4 ～7×10 -4 M, oxaliplatin mass concentration is 2-6 mg/ml.
2. The aqueous oxaliplatin solution according to claim 1, characterized in that: the molar ratio of citric acid to sodium citrate is 0.7:1.3.
3. The aqueous oxaliplatin solution according to claim 1, characterized in that: the molar concentration of citric acid in the aqueous solution is 3.3X10 -4 ～3.7×10 -4 M, molar concentration of sodium citrate is 6.3X10 -4 ～6.7×10 -4 M; further preferably, the molar concentration of citric acid in the aqueous solution is 3.5X10 -4 M, molar concentration of sodium citrate is 6.5X10 -4 M。
4. The aqueous oxaliplatin solution according to claim 1, characterized in that: the mass concentration of oxaliplatin is 5mg/ml.
5. The aqueous oxaliplatin solution according to claim 1, characterized in that: the pH value of the aqueous solution is 5.0-5.5; preferably, the pH value of the aqueous solution is 5.2-5.4; further preferably, the pH of the aqueous solution is 5.3.
6. The aqueous oxaliplatin solution according to any one of claims 1 to 5, characterized in that: comprises oxaliplatin, citric acid, sodium citrate and solvent water.
7. An aqueous oxaliplatin solution characterized by: wherein the catalyst does not contain impurity C; preferably, the aqueous oxaliplatin solution further satisfies at least one of the following: the content of the impurity A is less than or equal to 0.18 percent based on the marked amount of oxaliplatin; the content of the impurity B is less than or equal to 0.12 percent; the content of the impurity E is less than or equal to 0.16%; the total impurity content is less than or equal to 0.42 percent; preferably, the composition of the aqueous oxaliplatin solution is as defined in any one of claims 1 to 6.
8. The process for producing an aqueous oxaliplatin solution according to any one of claims 1 to 7, characterized in that: it comprises the following steps: dissolving oxaliplatin in water, adding citric acid and sodium citrate, and mixing uniformly; preferably, citric acid and sodium citrate are added as aqueous solutions; preferably, the preparation method further comprises the following steps: filling nitrogen into the prepared oxaliplatin aqueous solution until the dissolved oxygen amount is below 0.2 mg/L; preferably, the preparation method further comprises a filling step, and nitrogen is filled after filling until the oxygen content in the headspace is less than or equal to 3%.
9. Use of an aqueous oxaliplatin solution according to any one of claims 1 to 7 for the preparation of a liquid pharmaceutical formulation; preferably, the liquid pharmaceutical formulation is an injection.
10. Use of an aqueous solution of oxaliplatin as defined in any one of claims 1 to 7 for the manufacture of a medicament for the treatment of cancer.
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