Cordarone injection and its preparation method

Abstract

The application discloses a liquid preparation of desacetyllanatoside, wherein the pH value of a desacetyllanatoside aqueous solution is adjusted to 6.4-6.9 by a weak alkaline substance, and discloses a preparation method of the liquid preparation. The liquid preparation can obviously improve the stability of the desacetyllanatoside liquid preparation (for example, injection liquid and the like), effectively inhibits the degradation of the desacetyllanatoside in the liquid preparation under high-temperature conditions, reduces the generation of impurities C, impurities D and the like, and is helpful to better guarantee the product quality of the desacetyllanatoside liquid preparation and the medication safety of patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a deslanoside injection and its preparation method. Background Technology

[0002] Deslanoside is a cardiotonic drug with the chemical name 3-[[O-β-D-glucopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribohepyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribohepyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribohepyranosyl]oxo]-12,14-dihydroxy-cardoster-20(22)-enolactone (see: Chinese Pharmacopoeia 2015 edition, Part II). The main marketed formulation is deslanoside injection, which is used for heart failure, acute and chronic systolic heart failure, atrial fibrillation, paroxysmal tachycardia, etc., with good efficacy.

[0003] Literature reports that with the widespread use of deslanoside injection, adverse reactions such as arrhythmia, poor appetite, nausea, and vomiting have gradually increased. This is most likely caused by impurities and / or related substances in the injection, thus affecting the safety of deslanoside injection (Li Geyuan et al. Study on impurities in deslanoside injection [J]. Pharmaceutical and Clinical Research, 2011, 19(6):508-510.).

[0004] A study published in CN 112336687 A found that the deslanoside injection (deslanoside 0.2g, ethanol 80g, glycerin 175g, plus water for injection to 1000ml) of a product marketed in Japan had a pH of 6.91 and total impurities of 0.15% before high-temperature sterilization. After high-temperature sterilization at 121℃, the pH was 6.03 and the total impurities increased significantly to 22.3%.

[0005] The results of CN 112336687 A indicate that deslanoside injection is highly sensitive to temperature. High-temperature conditions during preparation and storage may lead to an increase in impurities and / or related substances in the injection. The proposed improvement is to add acidic substances such as hydrochloric acid, phosphoric acid, or sodium dihydrogen phosphate before high-temperature sterilization, thereby reducing the pH value of the injection before high-temperature sterilization from the original 6.91 to about 6.0 or lower, which can reduce the total impurity content after high-temperature sterilization at 121℃.

[0006] CN 112156069 A discloses a production process for deslanoside injection, which involves filling a mixture containing 0.2 mg / ml deslanoside, 0.076 g / ml ethanol, 0.149 g / ml glycerol and water for injection; wherein nitrogen purging is performed before and after filling.

[0007] The results of CN 112156069 A indicate that the total impurities after 10 days of high-temperature (60±2℃) storage without nitrogen filling were 4.0%, while the total impurities after 10 days of high-temperature (60±2℃) storage before and after filling with nitrogen were 3.2%, which is only slightly lower and does not seem to have a greater impact than the packaging material (boron ampoule) (see: Examples 1 and 2). The control of impurities and / or related substances is not ideal.

[0008] In view of this, the present invention is hereby proposed. Summary of the Invention

[0009] In view of the problems and / or deficiencies of the existing technology, the purpose of this invention is to provide a deslanoside liquid preparation (e.g., injection) and its preparation method, which can significantly improve the stability of the deslanoside liquid preparation, effectively inhibit the degradation of deslanoside in the liquid preparation under high temperature conditions, reduce the generation of impurities such as impurity C and impurity D, and help to better ensure the product quality of the deslanoside liquid preparation and the medication safety of patients.

[0010] The present invention provides a deslanoside liquid preparation, which is obtained by adjusting the pH value of the deslanoside aqueous solution to 6.4-6.9 (e.g., 6.4, 6.5, 6.6, 6.7, 6.8, etc.) with a weakly alkaline substance; wherein the weakly alkaline substance is an alkali metal acetate or an aqueous solution thereof.

[0011] Furthermore,

[0012] In any of the above technical solutions (deacetylanoside liquid preparation), the pH value of the deacetylanoside aqueous solution is adjusted to 6.5-6.8 using a weakly alkaline substance.

[0013] Furthermore,

[0014] In any of the above technical solutions (deacetylanoside liquid preparation), the deacetylanoside aqueous solution contains 0.05 to 0.5 mg / ml (e.g., 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, etc.) of deacetylanoside;

[0015] Preferably, the deslanoside aqueous solution contains 0.15–0.25 mg / ml of deslanoside;

[0016] More preferably, the deslanoside aqueous solution contains 0.2 ± 0.02 mg / ml of deslanoside.

[0017] Furthermore,

[0018] In any of the above technical solutions (deacetylanoside liquid preparation), the deacetylanoside aqueous solution contains ethanol, and the mass ratio of deacetylanoside to ethanol in the deacetylanoside aqueous solution is 1:100 to 1000 (e.g., 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, etc.).

[0019] Preferably, the mass ratio of deslanoside to ethanol in the deslanoside aqueous solution is 1:200-600.

[0020] More preferably, the mass ratio of deslanoside to ethanol in the deslanoside aqueous solution is 1:380-420.

[0021] Furthermore,

[0022] In any of the above technical solutions (deacetylanoside liquid preparation), the deacetylanoside aqueous solution contains glycerol, and the mass ratio of deacetylanoside to glycerol in the deacetylanoside aqueous solution is 1:100 to 500 (e.g., 1:100, 1:200, 1:300, 1:400, 1:500, etc.).

[0023] Preferably, the mass ratio of deslanoside to glycerol in the deslanoside aqueous solution is 1:100-350;

[0024] More preferably, the mass ratio of deslanoside to glycerol in the deslanoside aqueous solution is 1:180-220.

[0025] Furthermore,

[0026] In any of the above technical solutions (deacetylanoside liquid preparation), the alkali metal acetate is sodium acetate or potassium acetate; preferably, the alkali metal acetate is sodium acetate.

[0027] Furthermore,

[0028] In any of the above technical solutions (deacetylanoside liquid preparation), the weakly alkaline substance is an aqueous solution of alkali metal acetate;

[0029] Preferably, the concentration of the aqueous solution of the alkali metal acetate is 0.5 wt% to 10 wt% (e.g., 0.8 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, etc.);

[0030] More preferably, the concentration of the aqueous solution of the alkali metal acetate is 1.5 wt% to 2.5 wt%.

[0031] Furthermore,

[0032] In any of the above technical solutions (deacetylanoside liquid preparation), the deacetylanoside liquid preparation is a deacetylanoside injection.

[0033] The present invention also provides a method for preparing the deslanoside liquid preparation described in any one of the above claims, comprising the following steps: adjusting the pH value of the deslanoside aqueous solution to 6.4-6.9 (e.g., 6.4, 6.5, 6.6, 6.7, 6.8, etc.) with a weakly alkaline substance, then filling and sealing the solution to obtain the product.

[0034] Furthermore,

[0035] In any of the above technical solutions (preparation method of deslanoside liquid preparation), the deslanoside aqueous solution is prepared by the following method: dissolving or dispersing deslanoside in a mixture of ethanol, glycerol and water, and mixing well to obtain the solution.

[0036] The beneficial effects of this invention mainly include:

[0037] The deslanoside liquid formulation provided by this invention adjusts the pH of the deslanoside aqueous solution to 6.4–6.9 using a weakly alkaline substance (e.g., alkali metal acetate or its aqueous solution), which can significantly improve the stability of the deslanoside liquid formulation (almost unaffected by packaging materials), effectively inhibit the degradation of deslanoside in the liquid formulation under high temperature conditions (e.g., 60°C), and reduce the generation of impurities such as impurity C, impurity D, and / or impurity F. This helps to better ensure the product quality of deslanoside liquid formulations (e.g., injections) and the medication safety of patients. Attached Figure Description

[0038] Figure 1 The image shows the HPLC chromatogram of deslanoside injection obtained in Example 1 at 0°C.

[0039] Figure 2 The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 1 after a high-temperature test.

[0040] Figure 3 The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 1 after light irradiation.

[0041] Figure 4 The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 1 after a freeze-thaw test.

[0042] Figure 5 The image shows the HPLC chromatogram of deslanoside injection obtained in Example 2 at 0°C.

[0043] Figure 6The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 2 after a high-temperature test.

[0044] Figure 7 The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 3 after a high-temperature test.

[0045] Figure 8 The image shows the HPLC chromatogram of the deslanoside injection obtained in Example 4 after a high-temperature test. Detailed Implementation

[0046] The present invention will be clearly and completely described below with reference to specific embodiments. Those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0047] In this invention, unless otherwise specified, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0048] Regarding the definitions of terms used in this invention, unless otherwise stated, the initial definitions provided herein apply to the term throughout the text; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and / or context.

[0049] Example 1

[0050] Prepare deslanoside injection according to the formula in Table 1.

[0051] Table 1. Formulation of Deslanoside Injection

[0052] Deslanoside 200mg ethanol 80g glycerin 40g Water for Injection Add to 1000ml 2wt% sodium acetate aqueous solution Adjust the pH to 6.8.

[0053] Preparation method: Add the prescribed amount of deslanoside (200mg) to ethanol (80g) and part of the water for injection (e.g., 36ml). After completely dissolving at room temperature, add the prescribed amount of glycerol (40g), mix well, and add water for injection to make up to 1000ml. Measure the pH value with a pH meter (pH400 model, Anlailis Instruments Technology (Shanghai) Co., Ltd.) (result: pH = 5.56). Adjust the pH value to 6.8 with 2wt% sodium acetate aqueous solution. Fill and seal the solution in borosilicate glass ampoules to obtain deslanoside injection.

[0054] The prepared deslanoside injection (ampoules) was subjected to high temperature (60℃, 10 days) and light irradiation (total illuminance ≥1.2×10⁻⁶). 6The stability of the injection solution was evaluated by measuring its pH value, impurities, and related substances content before and after the test, using Lux·hr (continuous irradiation time of 10 days) and freeze-thaw cycles (two days at -18℃ and two days at 40℃, 3 cycles).

[0055] The content of impurities and related substances was detected by high performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020 Edition):

[0056] Column: Octadecylsilane-bonded silica gel as packing material (Kromasil 100-5-C18 column, pore size: Particle size: 5μm, 4.6mm × 250mm;

[0057] Mobile phase A: 1.36 g / L potassium dihydrogen phosphate aqueous solution, with 1 mL of triethylamine added, and the pH adjusted to 3.1 with phosphoric acid;

[0058] Mobile phase B: Acetonitrile-methanol-water = 50:20:20 (volume ratio);

[0059] Detection wavelength: 220nm;

[0060] Column temperature: 35℃;

[0061] Injection volume: 50 μL;

[0062] Flow rate: 1.0 mL / min;

[0063] Perform gradient elution according to Table 2:

[0064] Table 2. Gradient elution program for high performance liquid chromatography (HPLC)

[0065] 0 75 25 30 25 75 50 25 75 55 75 25 60 75 25

[0066] The measurement results are shown in Table 3.

[0067] Table 3. Results of pH value, impurities, and related substance content of the injection solution before and after the experiment.

[0068]

[0069] in,

[0070] For detailed measurement results at 0:00, please see [link / reference]. Figure 1 And Table 4.

[0071] Table 4. Detailed test results of deslanoside injection obtained in Example 1 at 0°C

[0072]

[0073] For detailed measurement results after the high-temperature (60℃, 10 days) test, please refer to [link / details]. Figure 2 See Table 5.

[0074] Table 5. Detailed test results of deslanoside injection obtained in Example 1 after high-temperature test.

[0075]

[0076] Detailed measurement results after the light exposure test and freeze-thaw test are available in the following sections: Figure 3 and Figure 4 .

[0077] Impurity C is digoxigenin (CAS No.: 1672-46-4), and its structural formula is as follows:

[0078]

[0079] Impurity D is digoxigenin monodigitoxoside (CAS No.: 5352-63-6), and its structural formula is as follows:

[0080]

[0081] Impurity F is digoxigenin bisdigitoxide (CAS No.: 5297-05-2), with the following structural formula:

[0082]

[0083] 130141 is digoxin (CAS No.: 20830-75-5), and its structural formula is as follows:

[0084]

[0085] Example 2

[0086] Prepare deslanoside injection according to the formula in Table 6.

[0087] Table 6. Formulation of Deslanoside Injection

[0088] Deslanoside 200mg ethanol 80g glycerin 40g Water for Injection Add to 1000ml 0.05 mol / L sodium hydroxide aqueous solution Adjust the pH to 6.8.

[0089] Preparation method: Add the prescribed amount of deslanoside (200mg) to ethanol (80g) and part of the water for injection (36ml). After completely dissolving at room temperature, add the prescribed amount of glycerol (40g), mix well, and add water for injection to make up to 1000ml. Measure the pH value with a pH meter (pH400 model) (result: pH=5.58). Adjust the pH value to 6.8 with 0.05mol / L sodium hydroxide aqueous solution. Fill and seal the solution in borosilicate glass ampoules to obtain deslanoside injection.

[0090] Following the same method as in Example 1, high temperature (60°C, 10 days) and light exposure (total illuminance ≥1.2 × 10⁻⁶) were applied. 6 Stability tests were conducted using Lux·hr (continuous irradiation for 10 days) and freeze-thaw cycles (two days at -18°C, two days at 40°C, 3 cycles), and the pH value, impurities, and content of related substances were determined.

[0091] The same high performance liquid chromatography method was used for detection (see Example 1 for chromatographic conditions), and the results are shown in Table 7.

[0092] Table 7. Results of pH value, impurities, and related substance content of the injection solution before and after the test.

[0093]

[0094] For detailed measurement results at 0:00, please refer to [link / reference]. Figure 5 For detailed measurement results after the high-temperature (60℃, 10 days) test, please refer to [link / reference]. Figure 6 .

[0095] Example 3

[0096] Prepare deslanoside injection according to the formula in Table 8.

[0097] Table 8. Formulation of Deslanoside Injection

[0098] Deslanoside 200mg ethanol 80g glycerin 40g Water for Injection Add to 1000ml 1wt% disodium hydrogen phosphate aqueous solution Adjust the pH to 6.8.

[0099] Preparation method: Add the prescribed amount of deslanoside (200mg) to ethanol (80g) and part of the water for injection (36ml). After completely dissolving at room temperature, add the prescribed amount of glycerol (40g), mix well, and add water for injection to make up to 1000ml. Measure the pH value with a pH meter (pH400 model) (result: pH=5.58). Adjust the pH value to 6.8 with 1wt% disodium hydrogen phosphate aqueous solution. Fill and seal the solution in borosilicate glass ampoules to obtain deslanoside injection.

[0100] Following the same method as in Example 1, high temperature (60°C, 10 days) and light exposure (total illuminance ≥1.2 × 10⁻⁶) were applied. 6Stability tests were conducted using Lux·hr (continuous irradiation for 10 days) and freeze-thaw cycles (two days at -18°C, two days at 40°C, 3 cycles), and the pH value, impurities, and content of related substances were determined.

[0101] The same high performance liquid chromatography method was used for detection (see Example 1 for chromatographic conditions), and the results are shown in Table 9.

[0102] Table 9. Results of pH value, impurities, and related substance content of the injection solution before and after the test.

[0103]

[0104] Detailed measurement results after the high-temperature (60℃, 10 days) test can be found in [link to relevant documentation]. Figure 7 .

[0105] Example 4

[0106] Prepare deslanoside injection according to the formula in Table 10.

[0107] Table 10. Formulation of Deslanoside Injection

[0108] Deslanoside 200mg ethanol 80g glycerin 40g Water for Injection Add to 1000ml

[0109] Preparation method: Add the prescribed amount of deslanoside (200mg) to ethanol (80g) and part of the water for injection (36ml). After completely dissolving at room temperature, add glycerol (40g), mix well, and add water for injection to make up to 1000ml. Measure the pH value with a pH meter (pH400 model) (result: pH=5.56). Fill and seal the solution in borosilicate glass ampoules to obtain deslanoside injection.

[0110] Following the same method as in Example 1, high temperature (60°C, 10 days) and light exposure (total illuminance ≥1.2 × 10⁻⁶) were applied. 6 Stability tests were conducted using Lux·hr (continuous irradiation for 10 days) and freeze-thaw cycles (two days at -18°C, two days at 40°C, 3 cycles), and the pH value, impurities, and content of related substances were determined.

[0111] The same high performance liquid chromatography method was used for detection (see Example 1 for chromatographic conditions), and the results are shown in Table 11.

[0112] Table 11. Results of pH value, impurities, and related substance content of the injection solution before and after the test.

[0113]

[0114] Detailed measurement results after the high-temperature (60℃, 10 days) test can be found in [link to relevant documentation]. Figure 8 .

[0115] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A deslanoside liquid formulation, characterized in that, The pH of the deslanoside aqueous solution is adjusted to 6.4-6.9 using a weakly alkaline substance; wherein the weakly alkaline substance is an alkali metal acetate or an aqueous solution thereof. The deslanoside aqueous solution contains 0.15–0.25 mg / ml of deslanoside; The deslanoside aqueous solution contains ethanol, and the mass ratio of deslanoside to ethanol in the deslanoside aqueous solution is 1:200-600. The deslanoside aqueous solution contains glycerol, and the mass ratio of deslanoside to glycerol in the deslanoside aqueous solution is 1:100-350. The alkali metal acetate is sodium acetate or potassium acetate; The deslanoside liquid preparation is a deslanoside injection.

2. The deslanoside liquid formulation according to claim 1, characterized in that, Adjust the pH of the deslanoside aqueous solution to 6.5–6.8 using a weakly alkaline substance.

3. The deslanoside liquid formulation according to claim 1 or 2, wherein the deslanoside aqueous solution contains 0.2 ± 0.02 mg / ml of deslanoside.

4. The deslanoside liquid formulation according to claim 1 or 2, characterized in that, The mass ratio of deslanoside to ethanol in the aqueous solution of deslanoside is 1:380-420.

5. The deslanoside liquid formulation according to claim 1 or 2, characterized in that, The mass ratio of deslanoside to glycerol in the aqueous solution of deslanoside is 1:180-220.

6. The deslanoside liquid formulation according to claim 1 or 2, characterized in that, The alkali metal acetate mentioned is sodium acetate.

7. The deslanoside liquid formulation according to claim 1 or 2, characterized in that, The weakly alkaline substance is an aqueous solution of an alkali metal acetate.

8. The deslanoside liquid formulation according to claim 7, characterized in that, The concentration of the aqueous solution of the alkali metal acetate is 0.5wt% to 10wt%.

9. The deslanoside liquid formulation according to claim 7, characterized in that, The concentration of the aqueous solution of the alkali metal acetate is 1.5wt% to 2.5wt%.

10. The method for preparing the deslanoside liquid formulation according to any one of claims 1 to 9, characterized in that, Includes the following steps: The pH of the deslanoside aqueous solution is adjusted to 6.4-6.9 with a weak alkaline substance, then filled and sealed to obtain the product; the deslanoside aqueous solution is prepared by dissolving or dispersing deslanoside in a mixture of ethanol, glycerol and water, and mixing well.

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