A preparation method of digoxin injection

Abstract

The invention discloses a preparation method of digoxin injection. The preparation method comprises dissolving digoxin in an ethanol aqueous solution with a volume concentration of 80%, and then mixing with other auxiliary materials to obtain digoxin injection. The preparation process provided by the invention can quickly dissolve a prescribed amount of digoxin in ethanol with a volume concentration of 80% in a short time, and the dissolution time is less than 1 minute. Moreover, by adding propylene glycol, the stability of digoxin injection and the solubility of digoxin in a mixed solvent system can be further improved, which is beneficial to the subsequent preparation of digoxin injection.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field, and more specifically, relates to a preparation method of digoxin injection. Background Art

[0002] Digoxin, chemical name: 3β-[[O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1,4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1,4)-2,6-dideoxy-β-D-ribo-hexopyranosyl]oxy]-12β,14β-dihydroxy-5β-cardiosteroid-20(22)enolactone, molecular formula: C 41 H 64 O 14 , molecular weight: 780.9. Digoxin can effectively strengthen myocardial contractility, slow heart rate, and inhibit cardiac conduction. It is widely used in the clinic to treat various acute and chronic heart failures, and to control the ventricular rate and supraventricular tachycardia of patients with atrial fibrillation and atrial flutter accompanied by rapid ventricular rate.

[0003] Digoxin is a colorless or white crystalline powder, which is easily soluble in pyridine, slightly soluble in dilute alcohol, very slightly soluble in chloroform, and insoluble in water or ether. Rapid dissolution of digoxin is beneficial to improving production efficiency, and more importantly, it is beneficial to ensure the stability of the digoxin content in the injection. However, pyridine is generally not allowed to be added to the injection, so higher requirements are placed on the dissolution of digoxin. CN14053222A reports a digoxin injection and a preparation method thereof. In the invention, digoxin is first evenly dispersed in a mixed solvent of ethanol and 1,2-propylene glycol, and then added to water for injection to completely dissolve it, with the shortest dissolution time being 4 minutes. Summary of the invention

[0004] The object of the present invention is to overcome at least one disadvantage of the prior art and provide a method for preparing digoxin injection.

[0005] The technical solution adopted by the present invention is:

[0006] The invention provides a method for preparing digoxin injection, which comprises the steps of dissolving digoxin in an ethanol aqueous solution with a volume concentration of 80%, and then mixing the digoxin with other auxiliary materials to prepare the digoxin injection.

[0007] The preparation method of digoxin injection provided by the present invention specifically comprises the following steps:

[0008] 1) dissolving a buffer and a pH adjuster in water for later use to obtain a buffer solution;

[0009] 2) adding digoxin to an 80% volume concentration ethanol aqueous solution and stirring until completely dissolved, and then adding propylene glycol to obtain a digoxin solution;

[0010] 3) Mix the buffer solution of step 1 and the digoxin solution of step 2, add water in proportion, and then filter, fill, and sterilize to obtain digoxin injection.

[0011] In some examples, the amount of digoxin used in step 2) is 0.24-0.26 g / L, and the amount of 80% volume concentration ethanol aqueous solution used is 78.9-87.3 g / L.

[0012] In some examples, the amount of propylene glycol used in step 2) is 389.5-430.5 g / L.

[0013] In some examples, in step 1), the buffer is anhydrous disodium hydrogen phosphate, and the pH adjuster is citric acid.

[0014] In some examples, in step 1), the amount of the buffer used is 1.68-1.72 g / L, and the amount of the pH adjuster used is 0.74-0.94 g / L.

[0015] In some examples, the dissolving temperature in step 1) is 25-35°C.

[0016] In some examples, the filtration step in step 3) is firstly circulating filtration through a microporous filter with a pore size of 0.22 μm, and then sterilizing filtration.

[0017] In some examples, the microporous filter is selected from any one of a polyethersulfone microporous filter, a polyvinylidene fluoride microporous filter, and a polytetrafluoroethylene microporous filter.

[0018] In some examples, the sterilization temperature in step 3) is 115-125°C.

[0019] The beneficial effects of the present invention are:

[0020] The invention provides a preparation process of digoxin injection, which can quickly dissolve digoxin, and the dissolution time is less than 1 minute. Since ethanol is volatile, the dissolution time of digoxin in 80% volume concentration ethanol is short, and it is sufficient to dissolve the prescribed amount of digoxin, and the addition of propylene glycol can further improve the stability of digoxin injection and the solubility of digoxin in a mixed solvent system. DETAILED DESCRIPTION

[0021] The following disclosure provides many different embodiments or examples for implementing different solutions of the present invention.

[0022] Comparison of solubility and dissolution time of digoxin in different organic solvents

[0023] An organic solvent (selected from any one of 100% volume concentration methanol, 100% volume concentration ethanol, propylene glycol, 100% volume concentration ethanol, 80% volume concentration ethanol aqueous solution, 60% volume concentration ethanol aqueous solution, 40% volume concentration ethanol aqueous solution, 20% volume concentration ethanol aqueous solution, 10% volume concentration ethanol aqueous solution, and 80% volume concentration methanol aqueous solution) is added into a container, and then digoxin is added and stirred until completely dissolved; the time required for digoxin to dissolve in different organic solvents is observed and recorded, and the solubility of digoxin in different solvents is tested, as shown in Table 1.

[0024] Table 1

[0025]

[0026] As can be seen from Table 1, surprisingly, although digoxin takes a long time to dissolve in ethanol and is insoluble in water, digoxin has the shortest dissolution time in 80% ethanol aqueous solution and has the greatest solubility, which can fully dissolve the prescribed amount of digoxin. Therefore, the use of 80% ethanol aqueous solution is conducive to faster and more dissolution of digoxin, which is beneficial to the subsequent preparation of digoxin injection.

[0027] Example 1

[0028] 1. The formula of digoxin injection is shown in Table 2:

[0029] Table 2

[0030]

[0031] 2. The preparation method is as follows:

[0032] (1) Add water for injection into container 1, then add anhydrous disodium hydrogen phosphate and citric acid, control the temperature at 25-35°C, stir until completely dissolved, and set aside;

[0033] (2) Add 80% ethanol into container 2, then add digoxin and stir until completely dissolved;

[0034] (3) adding propylene glycol to the solvent obtained in step (2) and stirring until completely dissolved;

[0035] (4) Add the solution obtained in step (1) to the solution obtained in step (3), stir evenly, take samples, and after the pH test is qualified (6.7-7.3), add water for injection to the total amount of the prepared solution;

[0036] (5) Pass the solution obtained in step (4) through a primary 0.22 μm polyvinylidene fluoride filter (filter element 10 inches), and stir and circulate for 10 to 15 minutes;

[0037] (6) The drug solution obtained in step (5) is filtered through a 0.22 μm polyvinylidene fluoride filter (filter element 5 inches) for terminal sterilization;

[0038] (7) Filling the ampoule with the drug solution obtained in step (6), and N2 is passed into the ampoule during filling;

[0039] (8) The drug solution obtained in step (7) is sterilized at 121° C. for 12 minutes to obtain digoxin injection.

[0040] 3. The performance test results of digoxin injection in experimental groups 1 to 4 are shown in Table 3.

[0041] Table 3

[0042]

[0043] The quality of the drug solution is stable within the pH range of 6.7 to 7.3. In the accelerated test, the growth of impurities in the drug solution with pH values ​​of 6.7 and 6.9 is higher than that in 7.2 and 7.3, but lower than the total impurity requirement of 4%, indicating that the digoxin injection provided by the present invention has high stability.

[0044] Example 2

[0045] 1. Prepare digoxin injection. The formula is shown in Table 4.

[0046] Table 4

[0047]

[0048] 2. Preparation method

[0049] The preparation method of this embodiment is consistent with that of embodiment 1.

[0050] 3. The performance test results of digoxin injections of experimental groups 5 to 6 are shown in Table 5. It can be seen that within the scope of the present invention, the amount of ethanol has almost no effect on the properties and impurities of digoxin.

[0051] Table 5

[0052]

[0053] Comparative Example 1

[0054] The formula provided in this comparative example is consistent with the formula of experimental group 1 in Example 1, and the specific preparation method is as follows:

[0055] (1) Add water for injection into container 1, then add anhydrous disodium hydrogen phosphate and citric acid, control the temperature at 25-35°C, stir until completely dissolved, and set aside;

[0056] (2) Add water for injection, part of the prescribed amount of propylene glycol and the prescribed amount of ethanol to container 2 in sequence, at which point the ratio of ethanol:propylene glycol:water is 5:5:2 (v / v / v), and stir until completely dissolved;

[0057] (3) Add digoxin to the solvent obtained in step (2) and stir until completely dissolved. Then add the remaining amount of propylene glycol and stir until completely dissolved;

[0058] (4) Add the solution obtained in step (1) to the solution obtained in step (3), stir evenly, take a sample, and after the pH test is qualified (6.7-7.3), add water for injection to the total amount of the prepared solution and stir evenly;

[0059] (5) The drug solution obtained in step (4) is subjected to circulation filtration, sterilization filtration, filling, and sterilization to obtain digoxin injection.

[0060] During the preparation of digoxin injection in Examples 1-2 and Comparative Example 1, the time required for dissolution of digoxin was observed and recorded, as shown in Table 6.

[0061] Table 6

[0062]

[0063] As shown in Table 6, digoxin can be rapidly dissolved in 80% ethanol, and the amount of ethanol does not affect the dissolution rate of digoxin, thereby improving the industrial production efficiency of digoxin injection.

[0064] The above is a further detailed description of the present invention, which should not be regarded as a limitation on the specific implementation of the present invention. For ordinary technicians in the technical field to which the present invention belongs, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.

Claims

1. A method for preparing digoxin injection, characterized in that: The following steps are involved: 1) dissolving a buffer and a pH adjuster in water for later use to obtain a buffer solution; 2) adding digoxin to an 80% volume concentration ethanol aqueous solution and stirring until completely dissolved, and then adding propylene glycol to obtain a digoxin solution; 3) Mixing the buffer solution of step 1 with the digoxin solution of step 2, adding water in proportion, and then filtering, filling, and sterilizing to obtain digoxin injection; Wherein, in the step 2), the amount of digoxin used is 0.24-0.26 g / L, the amount of 80% volume concentration ethanol aqueous solution used is 78.9-87.3 g / L, and the amount of propylene glycol used is 389.5-430.5 g / L.

2. The preparation method according to claim 1, characterized in that: In the step 1), the buffer is anhydrous disodium hydrogen phosphate, and the pH adjuster is citric acid.

3. The preparation method according to claim 2, characterized in that: In the step 1), the amount of the buffer used is 1.68-1.72 g / L, and the amount of the pH adjuster used is 0.74-0.94 g / L.

4. The preparation method according to claim 1, characterized in that: The dissolving temperature in step 1) is 25-35°C.

5. The preparation method according to claim 1, characterized in that: The filtration step in step 3) is to first perform circulation filtration through a microporous filter with a pore size of 0.22 μm, and then perform sterilization filtration.

6. The preparation method according to claim 5, characterized in that: The microporous filter is selected from any one of a polyethersulfone microporous filter, a polyvinylidene fluoride microporous filter and a polytetrafluoroethylene microporous filter.

7. The preparation method according to claim 1, characterized in that: The sterilization temperature in step 3) is 115-125°C.

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