Digoxin injection and preparation method thereof

Abstract

The present invention relates to digoxin injection and a preparation method thereof. The digoxin injection is preferably in the specification of 2ml:0.5mg. The digoxin injection of the present invention has a small amount of alcohol auxiliary materials and good stability, which is significantly better than the prior art and can improve the safety of medication and the convenience of production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to digoxin injection and a preparation method thereof. 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, also known as isohydroxydigitoxin; Digoxin; Cardiotonic; Isohydroxydigitoxin, digoxin is a medium-acting cardiac glycoside drug. During treatment, its effect on the heart is manifested as positive inotropic effect, slowing heart rate and inhibiting cardiac conduction. It is suitable for low-output congestive heart failure, atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. It is used for various acute and chronic heart failures, supraventricular tachycardia, atrial fibrillation and flutter, etc. It is rapidly and completely absorbed orally, with a bioavailability of more than 90%. The plasma drug concentration reaches a peak value 1 hour after taking the drug, and it reaches a significant effect after 4 hours, and the peak effect is reached after 6 to 12 hours. The serum therapeutic concentration is 15 to 25 ng / ml, and the plasma protein binding rate is 97%. It mainly disappears through liver microsomal enzyme metabolism, and the elimination half-life is generally 4 to 7 days. It is excreted by bile, and after recycling, it is excreted by urine. It is usually taken orally, and intravenous injection is used for patients with severe heart failure. Common dosage forms include injections, oral solutions, etc. Digoxin is a colorless or white crystalline powder, which is easily soluble in pyridine, slightly soluble in ethanol, very slightly soluble in propylene glycol and chloroform, and insoluble in water. In order to increase the solubility of digoxin, ethanol is generally used to dissolve digoxin injection. However, ethanol has an inhibitory effect on the central nervous system, so there are strict restrictions on the use of ethanol. For example, the Chinese Pharmacopoeia 2020 edition has clear restrictions on the ethanol content in digoxin oral solution, and the content limit is 9-11%. The ethanol content in the digoxin liquid preparation prepared by the prior art is generally around 10%. For example, Example 4 of Chinese Application No. 201811634576.8 contains 10% ethanol and 20% Propylene glycol; Chinese application 202111642386.2 In order to reduce the amount of ethanol used, the prepared digoxin injection contains 5-10% ethanol. Although the amount of ethanol used is reduced, the amount of propylene glycol used is as high as 20-50%. Propylene glycol also has the disadvantage of inhibiting the central nervous system. Therefore, this solution cannot solve the problems of the prior art well. At the same time, the use of higher concentrations of ethanol and propylene glycol in the preparation process of digoxin injection requires the production workshop to have explosion-proof functions, and the company's production costs and safety risks are very high. Summary of the invention

[0003] In view of the above technical problems, a digoxin injection with reduced alcohol excipient usage has a positive effect on the application of digoxin. The inventors have obtained a digoxin injection in the process of long-term and extensive research on digoxin. The injection can greatly reduce the alcohol usage and has extremely high quality stability, increases the safety of medication, and is convenient for production, which is significantly better than the existing technology.

[0004] The technical solution provided by the present invention is:

[0005] Digoxin injection is composed of digoxin, thiourea, sodium glycerophosphate, ethanol, pH adjuster and water for injection.

[0006] The concentration of digoxin is 0.025%, the content of ethanol is 2.5%, the content of thiourea is 0.05-0.1%, and the content of sodium glycerophosphate is 0.04-0.06%.

[0007] The inventor unexpectedly discovered through a large number of experiments that by adding thiourea and sodium glycerophosphate, digoxin can be dissolved while maintaining extremely high stability while significantly reducing the amount of ethanol used.

[0008] Preferably, the content of thiourea is 0.1% and the content of sodium glycerophosphate is 0.06%.

[0009] Preferably, the specification of digoxin injection is 2ml:0.5mg.

[0010] Preferably, the pH adjuster is hydrochloric acid solution or sodium hydroxide solution.

[0011] The present invention also provides a method for preparing digoxin injection, comprising the following steps:

[0012] 1. Mix digoxin and thiourea, add water for injection, 70-75℃, stir and disperse to obtain the first solution;

[0013] 2. Add ethanol to water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0014] 3. Gradually add the second solution into the first solution, stir continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 6.5-7.5 with a pH adjuster, and heat the water for injection to the full amount while stirring continuously;

[0015] 4. Filter, fill according to specifications and sterilize to obtain digoxin injection.

[0016] The present invention adopts thiourea, sodium glycerophosphate and ethanol as auxiliary materials of digoxin injection. The use of the two auxiliary materials, thiourea and sodium glycerophosphate, can greatly reduce the amount of ethanol while completely dissolving digoxin, and no propylene glycol is used. The combined use of the two has an unexpected effect, especially the combination of 0.1% thiourea and 0.06% sodium glycerophosphate, which has the best effect. While dissolving digoxin, the stability of digoxin can be significantly improved.

[0017] The preparation method of digoxin injection of the present invention comprises the following steps: firstly mixing digoxin and thiourea, stirring and dispersing with water, and then adding a mixed solution of ethanol and sodium glycerophosphate to stir and dissolve. This process step also plays a key role in the preparation of digoxin injection. Changing the operation steps will cause the digoxin to fail to dissolve smoothly.

[0018] Preferably, the pH is adjusted to 7.0.

[0019] Preferably, the digoxin injection is filtered using a 0.22 μm filter membrane.

[0020] Preferably, the sterilization conditions for digoxin injection are: moist heat sterilization at 121°C for 15 minutes. DETAILED DESCRIPTION

[0021] In order to make the present invention easier to understand, specific embodiments of the present invention will be further described below. The specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0022] Example 1 Preparation of digoxin injection

[0023] Prescription: Digoxin 0.25g

[0024] Anhydrous ethanol 25ml

[0025] Thiourea 0.5g

[0026] Sodium glycerophosphate 0.4g

[0027] Add water for injection to 1000ml

[0028] Made into 500 pieces

[0029] Specific preparation method:

[0030] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0031] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0032] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0033] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0034] Example 2 Preparation of digoxin injection

[0035] Prescription: Digoxin 0.25g

[0036] Anhydrous ethanol 25ml

[0037] Thiourea 0.7g

[0038] Sodium glycerophosphate 0.5g

[0039] Add water for injection to 1000ml

[0040] Made into 500 pieces

[0041] Specific preparation method:

[0042] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0043] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0044] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0045] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0046] Example 3 Preparation of digoxin injection

[0047] Prescription: Digoxin 0.25g

[0048] Anhydrous ethanol 25ml

[0049] Thiourea 0.5g

[0050] Sodium glycerophosphate 0.5g

[0051] Add water for injection to 1000ml

[0052] Made into 500 pieces

[0053] Specific preparation method:

[0054] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0055] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0056] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0057] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0058] Example 4 Preparation of digoxin injection

[0059] Prescription: Digoxin 0.25g

[0060] Anhydrous ethanol 25ml

[0061] Thiourea 0.5g

[0062] Sodium glycerophosphate 0.6g

[0063] Add water for injection to 1000ml

[0064] Made into 500 pieces

[0065] Specific preparation method:

[0066] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0067] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0068] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0069] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0070] Example 5 Preparation of digoxin injection

[0071] Prescription: Digoxin 0.25g

[0072] Anhydrous ethanol 25ml

[0073] Thiourea 1g

[0074] Sodium glycerophosphate 0.4g

[0075] Add water for injection to 1000ml

[0076] Made into 500 pieces

[0077] Specific preparation method:

[0078] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0079] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0080] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0081] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0082] Example 6 Preparation of Digoxin Injection

[0083] Prescription: Digoxin 0.25g

[0084] Anhydrous ethanol 25ml

[0085] Thiourea 1.0g

[0086] Sodium glycerophosphate 0.6g

[0087] Add water for injection to 1000ml

[0088] Made into 500 pieces

[0089] Specific preparation method:

[0090] 1. Mix the prescribed amount of digoxin and thiourea, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0091] 2. Add anhydrous ethanol to 100 ml of water for injection, stir evenly, then add sodium glycerophosphate and stir to dissolve to obtain the second solution;

[0092] 3. Gradually add the second solution into the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 7.0 with hydrochloric acid or sodium hydroxide solution, and then add water for injection to the full amount while stirring continuously.

[0093] 4. Filter through a 0.22 μm filter membrane, fill into ampoules according to specifications, seal, and sterilize at 121°C for 15 minutes to obtain digoxin injection.

[0094] Comparative Example 1 Preparation of Digoxin Injection

[0095] Prescription: Digoxin 0.25g

[0096] Anhydrous ethanol 25ml

[0097] Thiourea 0.4g

[0098] Sodium glycerophosphate 0.4g

[0099] Add water for injection to 1000ml

[0100] Made into 500 pieces

[0101] Specific preparation test results, referring to the preparation method of the present application, the amount of thiourea used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0102] Comparative Example 2 Preparation of Digoxin Injection

[0103] Prescription: Digoxin 0.25g

[0104] Anhydrous ethanol 25ml

[0105] Thiourea 0.5g

[0106] Sodium glycerophosphate 0.3g

[0107] Add water for injection to 1000ml

[0108] Made into 500 pieces

[0109] Specific preparation test results, referring to the preparation method of the present application, the amount of sodium glycerophosphate used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0110] Comparative Example 3 Preparation of Digoxin Injection

[0111] Prescription: Digoxin 0.25g

[0112] Anhydrous ethanol 25ml

[0113] Thiourea 1.1g

[0114] Sodium glycerophosphate 0.6g

[0115] Add water for injection to 1000ml

[0116] Made into 500 pieces

[0117] Specific preparation test results, referring to the preparation method of the present application, the amount of thiourea used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0118] Comparative Example 4 Preparation of Digoxin Injection

[0119] Prescription: Digoxin 0.25g

[0120] Anhydrous ethanol 25ml

[0121] Thiourea 1g

[0122] Sodium glycerophosphate 0.7g

[0123] Add water for injection to 1000ml

[0124] Made into 500 pieces

[0125] Specific preparation test results, referring to the preparation method of the present application, the amount of sodium glycerophosphate used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0126] Comparative Example 5 Preparation of Digoxin Injection

[0127] Prescription: Digoxin 0.25g

[0128] Anhydrous ethanol 25ml

[0129] Thiourea 0.4g

[0130] Sodium glycerophosphate 0.3g

[0131] Add water for injection to 1000ml

[0132] Made into 500 pieces

[0133] Specific preparation test results, referring to the preparation method of the present application, the dosage of thiourea and sodium glycerophosphate exceeded the scope of the present application, and digoxin could not be completely dissolved.

[0134] Comparative Example 6 Preparation of Digoxin Injection

[0135] Prescription: Digoxin 0.25g

[0136] Anhydrous ethanol 25ml

[0137] Thiourea 1.1g

[0138] Sodium glycerophosphate 0.7g

[0139] Add water for injection to 1000ml

[0140] Made into 500 pieces

[0141] Specific preparation test results, referring to the preparation method of the present application, the dosage of thiourea and sodium glycerophosphate exceeded the scope of the present application, and digoxin could not be completely dissolved.

[0142] Comparative Example 7 Preparation of Digoxin Injection

[0143] Prescription: Digoxin 0.25g

[0144] Anhydrous ethanol 24ml

[0145] Thiourea 1.0g

[0146] Sodium glycerophosphate 0.6g

[0147] Add water for injection to 1000ml

[0148] Made into 500 pieces

[0149] Specific preparation test results, referring to the preparation method of the present application, the amount of anhydrous ethanol used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0150] Comparative Example 8 Preparation of Digoxin Injection

[0151] Prescription: Digoxin 0.25g

[0152] Anhydrous ethanol 26ml

[0153] Thiourea 1.0g

[0154] Sodium glycerophosphate 0.6g

[0155] Add water for injection to 1000ml

[0156] Made into 500 pieces

[0157] Specific preparation test results, referring to the preparation method of the present application, the amount of anhydrous ethanol used exceeds the scope of the present application, and digoxin cannot be completely dissolved.

[0158] Comparative Example 9 Preparation of Digoxin Injection

[0159] Prescription: Digoxin 0.25g

[0160] Anhydrous ethanol 25ml

[0161] Thiourea 1.0g

[0162] Sodium glycerophosphate 0.6g

[0163] Add water for injection to 1000ml

[0164] Made into 500 pieces

[0165] Specific preparation method:

[0166] 1. Mix the prescribed amount of digoxin, thiourea and sodium glycerophosphate, add 200 ml of water for injection, at 70-75°C, stir and disperse to obtain the first solution;

[0167] 2. Add anhydrous ethanol to 100 ml of water for injection and stir evenly to obtain the second solution;

[0168] 3. The second liquid was gradually added to the first liquid, and the mixture was stirred continuously at 40-45° C. Digoxin could not be completely dissolved, and the preparation failed. The preparation process of the present invention was adjusted, but the digoxin injection of the present application could not be obtained.

[0169] Judging from the test results of the embodiments and comparative examples (the comparative examples exceed the technical solution conditions of the present application by many means, which are not listed one by one in the present application due to space limitations, and the test results are consistent with the listed comparative examples), the specific dosage of the digoxin auxiliary materials anhydrous ethanol, thiourea, and sodium glycerophosphate and the preparation method of the present application can successfully prepare digoxin injection on the basis of reducing the amount of ethanol. If the technical solution of the present application is exceeded, digoxin injection cannot be prepared.

[0170] The present invention provides the following test and comparison results:

[0171] Sample 1-6: Digoxin injection prepared in Example 1-6 of the present invention

[0172] Sample 7: Commercially available digoxin injection

[0173] Samples 1 to 7 were subjected to accelerated stability tests (40℃±2℃, RH 75%±5%), with samples taken at 0, 1, 2, 3, and 6 months. The test results were shown in Table 1-2 in reference to the method for digoxin injection in the Chinese Pharmacopoeia 2020 edition.

[0174] Table 1 Results of accelerated test of digoxin injection of samples 1-3

[0175]

[0176] Table 2 Results of accelerated test of digoxin injection of samples 4-7

[0177]

[0178] It can be seen from the results in Table 1-2 that the digoxin injection prepared by the present invention has significantly improved stability compared with the prior art, and Example 6 has the best stability.

Claims

1. Digoxin injection, characterized in that Composed of digoxin, thiourea, sodium glycerophosphate, The digoxin content is 0.025%, the ethanol content is 2.5%, the thiourea content is 0.05-0.1%, and the sodium glycerophosphate content is 0.04-0.06%. The preparation method comprises the following steps: (1) Mix digoxin and thiourea, add water for injection, stir and disperse at 70-75°C to obtain the first solution; (2) adding ethanol to water for injection, stirring evenly, and then adding sodium glycerophosphate and stirring to dissolve, to obtain a second solution; (3) Gradually add the second solution to the first solution, stirring continuously at 40-45°C until digoxin is completely dissolved, adjust the pH value to 6.5-7.5 with a pH adjuster, and then heat the water for injection to the full amount while stirring continuously; (4) Filter, fill according to specifications, and sterilize to obtain digoxin injection.

2. The digoxin injection according to claim 1, characterized in that The content of thiourea is 0.1%.

3. The digoxin injection according to claim 1, characterized in that The content of the sodium glycerophosphate is 0.06%.

4. The digoxin injection according to any one of claims 1 to 3, characterized in that The pH regulator is a hydrochloric acid solution or a sodium hydroxide solution.

5. The digoxin injection according to any one of claims 1 to 3, characterized in that: The specification of the digoxin injection is: 2ml: 0.5mg.

6. The digoxin injection according to claim 1, characterized in that: Preparation method step (3) adjusting the pH value to 7.0 with a pH adjuster.

7. The digoxin injection according to claim 1, characterized in that: The sterilization conditions described in step (4) of the preparation method are: moist heat sterilization at 121° C. for 15 minutes.

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