CN117045598A

CN117045598A - Preparation method of digoxin injection with stable quality

Info

Publication number: CN117045598A
Application number: CN202311095207.7A
Authority: CN
Inventors: 张振栋; 曹韩韩; 刘晓; 梁屹
Original assignee: Shanghai Xudong Haipu Pharmaceutical Co ltd
Current assignee: Shanghai Xudong Haipu Pharmaceutical Co ltd
Priority date: 2023-08-29
Filing date: 2023-08-29
Publication date: 2023-11-14

Abstract

A preparation method of a stable quality digoxin injection comprises the steps of preparing 75-85 wt.% ethanol solution from medicinal ethanol with a prescription dosage, adding digoxin into the ethanol solution, and stirring to dissolve the digoxin solution to obtain a digoxin solution; preparing a buffer solution, uniformly mixing the obtained digoxin solution, propylene glycol and the buffer solution, adjusting the pH to 6.8-7.5, and adding water for injection to the total preparation amount; filtering with fluorine-lined filter material, packaging, and terminal sterilizing to obtain digoxin injection. In the invention, the dissolution speed of the digoxin is high, the dissolution time is less than 5 minutes, the compatibility of the digoxin injection and a production assembly is good, no extract exists after the digoxin injection is placed, the quality of the injection is stable, the content of related substances of a finished product preparation is less than 2.0 percent, the content is more than 97.0 percent, the pH value is stable, and the injection does not have extract after the injection is placed under the acceleration condition of 75 percent RH at 40 ℃ for 6 months.

Description

Preparation method of digoxin injection with stable quality

Technical Field

The invention belongs to the field of pharmaceutical product manufacturing, and particularly relates to a preparation method of a digoxin injection with stable quality, which has the advantages of high dissolution rate of digoxin, stable pH value and stable quality, and no extract after being placed.

Background

Digoxin belongs to the digitalis class of cardiotonic drugs, and digoxin injection (Digoxin Injection) is mainly used for acute and chronic cardiac insufficiency and for controlling atrial fibrillation with rapid ventricular rate, ventricular rate in atrial flutter patients and supraventricular tachycardia.

Digoxin is white crystal or crystalline powder, odorless, soluble in pyridine, slightly soluble in ethanol, slightly soluble in chloroform and insoluble in water or diethyl ether, and the characteristic of poor solubility ensures that the preparation of the digoxin injection has a large technical barrier and influences the commercial production efficiency of the digoxin injection.

The original preparation formula of the digoxin injection comprises an organic solvent of ethanol and propylene glycol, and in the preparation and production processes, the solubility of raw materials is poor, the production efficiency is reduced in the production process, and the precipitation of active ingredients in the feeding process is possibly caused, so that the quality of the product is unqualified.

The use of plastic components such as filter cartridges, silicone tubes, etc. is unavoidable in the production of injectables, and the plastic component systems used in the production of chemical injectables may come into contact with liquids and interact, resulting in the production and accumulation of the associated leachates. The continued presence of the extract in the liquid and eventual delivery to the final product may affect product quality and/or patient safety.

In the commercial production process of the digoxin injection, according to the production process of the product, the contact time of the liquid medicine and plastic components such as the filter element is up to 20 hours at most, and the content of the organic solvent in the digoxin injection is about 50%, so that the risk of incompatibility of the liquid medicine and the plastic components is increased, the extract is possibly generated in the production process, the quality of the product is influenced, and finally the quality of the product is disqualified.

Disclosure of Invention

The invention aims to provide a preparation method of a digoxin injection with stable quality, which solves the problem of dissolving digoxin, and in the method, the dissolving rate of the digoxin is greatly accelerated, the dissolving time is less than 5 minutes until the digoxin is clarified, no precipitation is caused later, the pH value is stable, the quality is stable, no extract exists after the liquid medicine is contacted with a component for 24 hours, and the impurity content is still less than 2% after long-term standing.

In order to achieve the above purpose, the present invention provides the following technical solutions:

a preparation method of a digoxin injection with stable quality comprises the following steps:

1) Preparing 75-85 wt.% ethanol solution from medicinal ethanol with a prescription dosage, adding digoxin into the ethanol solution, and stirring to dissolve the digoxin solution to obtain a digoxin solution;

2) Taking water for injection with the total preparation amount of 30-40 vol.%, adding a prescribed amount of buffering agent, and stirring until the buffering agent is completely dissolved to obtain a buffer solution; uniformly mixing the digoxin solution obtained in the step 1), propylene glycol and buffer solution, regulating the pH to 6.8-7.5, and adding water for injection to the total preparation amount;

3) Filtering the solution obtained in the step 2), filling, and sterilizing at a terminal to obtain the digoxin injection;

in the prescription, the content of digoxin is 0.1-0.25 mg/ml, the content of ethanol is 9.0-11.0 vol.% and the content of propylene glycol is 38.0-42.0 vol.%.

Preferably, in step 1), the ethanol content in the ethanol solution is 78-82 wt.%.

In step 2), the buffer is anhydrous disodium hydrogen phosphate-anhydrous citric acid buffer pair or potassium dihydrogen phosphate-sodium hydroxide buffer pair.

Further, anhydrous disodium hydrogen phosphate in the buffer solution is added in the form of a hydrate thereof, and anhydrous citric acid is added in the form of a hydrate thereof; or the potassium dihydrogen phosphate is added in the form of its hydrate.

Preferably, in step 1), the dissolution temperature of the stirred solution is 20-70 ℃ and the solution time is less than 10 minutes.

In the step 1), the dissolution temperature of the stirring solution is 25-40 ℃, and the dissolution time is less than 5 minutes.

Further, in the step 2), after the buffer solution is obtained, the prescribed amount of propylene glycol is added thereto, and stirred until uniformly mixed, so as to prepare a stabilizer solution, and the digoxin solution and the stabilizer solution are mixed.

In the step 3), a filter element or a filter membrane lined with fluorine is adopted during the filtration.

Further, the filter element is a hydrophilic polytetrafluoroethylene filter element or a polyvinylidene fluoride filter element.

Preferably, in step 3), the sterilization temperature is 121 ℃ and the sterilization time is 15 minutes.

In the auxiliary material solution of the digoxin injection, ethanol is used as a solubilizer, propylene glycol is used as an auxiliary solubilizer or a stabilizer, the dosage is mainly formulated by reference to a reference preparation on the market, and precipitation or other problems can be caused when the dosage is reduced.

The inventors found through researches that digoxin has poor solubility in low-concentration ethanol-water solutions, for example, the solubility is only 0.05-1.34 mg/ml when the solubility is 10-50 wt.% ethanol-water solution, and the solubility is poor when the ethanol content is too high, for example, the solubility is 3.20mg/ml when the solubility is 95wt.% ethanol-water solution; digoxin has poor solubility in propylene glycol, the solubility is 0.47mg/ml, and in a propylene glycol-water solution in the range of 40-80%, the solubility of digoxin gradually increases with the increase of the propylene glycol content, however, the increase is very limited, and only increases from 0.08mg/ml to 0.60mg/ml; the solubility of digoxin in the mixed solvent of ethanol-propylene glycol (1:4, v/v) is about 1.63mg/ml at 40 ℃, however, after water is added into the system to form an ethanol-propylene glycol-water (1:4:5, v/v) system, the solubility of digoxin in the system is about 0.3 mg/ml.

In order to solve the problem of dissolving digoxin, the method comprises the steps of preparing 75-85% of alcohol solution from a prescription amount of alcohol solution, adding digoxin into the alcohol solution, quickly dissolving the digoxin, wherein the solubility of the digoxin is up to 6.96mg/ml, which is far higher than the solubility of the digoxin in water, propylene glycol and a mixed solvent of ethanol and propylene glycol, and the dissolving time at room temperature is less than 5 minutes, so that the problem of the solubility of the digoxin injection in the commercial production process is solved, micronization treatment or special preparation technology is not needed, and a solubilizer is not needed to be additionally added, the production process of the digoxin injection is controlled within 1 hour, the production efficiency is improved, the problem caused by indissoluble active ingredients is avoided, the quality is stable after long-term storage, and no precipitation is caused.

The invention controls the kind and the dosage of buffering agent, adjusts the pH value of the solution to keep the quality of the injection stable, controls the growth of the related substances at high temperature, and controls the growth of the related substances after the digoxin injection is placed at high temperature for 10 days when the pH value of the digoxin injection is lower than 6.8, wherein the growth amplitude of the related substances is large after the digoxin injection is placed at high temperature of 60 ℃; when the pH value of the preparation is between 6.8 and 7.5, related substances are not changed obviously after the preparation is placed for 10 days at the high temperature of 60 ℃, and the quality of the preparation is stable.

In the invention, the influence of filtering materials on the quality of products is examined, and the inventor finds that the filtering membrane made of conventional materials is adopted to filter digoxin liquid medicine, and unknown impurities in the liquid medicine are leached out; the solution obtained in the step 2) is filtered by using a fluorine-lined filter element, so that the generation of extract can be avoided, the compatibility of the digoxin injection and a production assembly is good, the selected filter membrane is free from the generation of extract after being soaked in the digoxin injection liquid medicine for 24 hours, the stable quality of the preparation is ensured, and the filter element made of polyvinylidene fluoride or hydrophilic polytetrafluoroethylene is preferred.

Compared with the prior art, the invention has the following beneficial effects:

according to the invention, through setting reasonable preparation steps, proper dissolution liquid is screened out, the concentration of ethanol in the dissolution liquid is controlled, ethanol is firstly prepared into 75-85 wt.% of ethanol solution, the ethanol solution capable of rapidly dissolving digoxin is obtained, the solution clearing time of the digoxin in the solution at room temperature is less than 5 minutes, the solubility can reach 6.96mg/ml, and is far higher than the solubility of the digoxin in water, propylene glycol and ethanol-propylene glycol mixed solvents, the total time of the commercial production preparation process of the digoxin injection is only about 1 hour, the central control content of the product is stabilized at 97% -103%, and the quality of the digoxin injection after terminal sterilization is stable.

In the invention, the pH value of the solution is regulated to be 6.8-7.5, the growth of related substances at high temperature is controlled, and the related substances have no obvious change after being placed for 10 days at the high temperature of 60 ℃; the fluorine lining filter core is used for filtering, the compatibility of the digoxin injection and the production assembly is good, no extract exists after the digoxin injection is placed, the injection quality is stable, and the content of related substances of a finished product preparation is less than 2.0% and is more than 97.0% in 6 months under the acceleration condition of 40 ℃ and RH 75%.

Detailed Description

The invention is further illustrated below with reference to specific examples.

The parts not described in detail in the following examples can be carried out according to the literature descriptions in the field and the routine experimental procedures or conditions of injection, and the used auxiliary materials are conventional pharmaceutical auxiliary materials unless specified, and 95% pharmaceutical ethanol (v/v) is used for preparation in the examples.

Digoxin injection original grinding preparation, manufacturer: covis pharma BV.

Example 1

Digoxin injection formulations, see table 1.

TABLE 1

Raw and auxiliary materials	Dosage of	Content of
			Digoxin	0.05g	0.25mg/ml
Medicinal ethanol	21.0ml	10.5vol.％
			Propylene glycol	80.0ml	40.0vol.％
Anhydrous disodium hydrogen phosphate	0.34g	0.17wt.％
			Citric acid	0.175g	0.0875wt.％
Water for injection	Added to 200ml (100 pieces)	N/A

In Table 1, the ethanol used in the preparation was 95% medicinal ethanol (v/v), the medicinal ethanol content was 10.5vol.%, and the theoretical ethanol content in the prepared digoxin injection preparation was 10 vol.%.

The preparation method comprises the following steps:

according to the prescription of Table 1, the medicinal ethanol with the prescription amount is measured, and the water for injection is added to 25.0ml to prepare an ethanol solution with 80 wt%; adding the prescribed amount of digoxin into the 80wt.% ethanol solution, magnetically stirring at 40 ℃, and dissolving and clarifying within 2 minutes to obtain a digoxin solution;

adding anhydrous disodium hydrogen phosphate and citric acid with a prescription amount into 80ml of water for injection, stirring and dissolving at 40 ℃ to obtain a buffer solution, adding propylene glycol with a prescription amount, and stirring until the solution is uniform to obtain a stabilizer solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, measuring the pH value to be 6.8, adding water for injection until the total amount is prepared, filtering by using a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ for 15min under high pressure to obtain the digoxin injection;

the detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.8, content: 98.8%, related substances: impurity C0.05%, impurity D not detected, impurity F0.16%, total impurities 1.3% (only some impurities listed below).

Example 2

Prescription:

in the prescription of the digoxin injection shown in table 1, except that the dosage of the medicinal ethanol is adjusted to 18.9ml and the content of the medicinal ethanol is 9.5vol%, the rest compositions and the dosage are all shown in table 1, and the theoretical ethanol content in the preparation is 9 vol%.

The preparation method comprises the following steps:

according to the adjusted prescription of the table 1, measuring the medicinal ethanol with the prescription amount, and adding water for injection to prepare 75 weight percent ethanol solution; adding the prescribed amount of digoxin into 75wt.% ethanol solution, magnetically stirring at 25 ℃, and dissolving and clarifying within 2 minutes to obtain a digoxin solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, measuring the pH value to be 6.9, adding water for injection until the total amount is prepared, filtering by using a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ for 15min under high pressure to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.9, content: 98.0%, related substances: impurity C0.05%, impurity D not detected, impurity F0.13%, total impurity 1.2%.

Example 3

Prescription:

in the prescription of the digoxin injection shown in table 1, except that the dosage of the medicinal ethanol is adjusted to be 23.2ml and the content is 11.6 vol%, the rest compositions and the dosage are all referred to table 1, and the theoretical ethanol content in the preparation is 11vol%.

The preparation method comprises the following steps:

according to the adjusted prescription of the table 1, taking the medicinal ethanol with the prescription amount, adding water for injection, and preparing an ethanol solution with the weight of 85%; adding the prescribed amount of digoxin into an ethanol solution with the concentration of 85wt.%, magnetically stirring at 70 ℃ for 2 minutes until the digoxin is dissolved and clarified, and obtaining a digoxin solution;

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.9, content: 98.3%, related substances: impurity C0.05%, impurity D not detected, impurity F0.12%, total impurity 1.2%.

Example 4

Prescription:

table 1 is referred to for the compositions and amounts of the formulations of digoxin injections shown in table 1, except that the propylene glycol amount was adjusted to 76.0ml and the content was 38 vol%.

The preparation method comprises the following steps:

according to the adjusted prescription of the table 1, taking the medicinal ethanol with the prescription amount, adding water for injection, and preparing an ethanol solution with the weight of 80%; adding the prescribed amount of digoxin into an 80wt.% ethanol solution, magnetically stirring at 40 ℃ for 2 minutes until the digoxin is dissolved and clarified to obtain a digoxin solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, measuring the pH value to be 6.8, adding water for injection until the total amount is prepared, filtering by using a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ for 15min under high pressure to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.8, content: 99.7%, related substances: impurity C0.05%, impurity D not detected, impurity F0.17%, total impurity 1.3%.

Example 5

Prescription:

table 1 is referred to for the compositions and amounts of the formulations of digoxin injections shown in table 1, except that the propylene glycol amount was adjusted to 84ml and the content was 42 vol%.

The preparation method comprises the following steps:

according to the adjusted prescription of the table 1, taking the medicinal ethanol with the prescription amount, adding water for injection to 25.0ml, and preparing an ethanol solution with the weight of 80%; adding the prescribed amount of digoxin into an 80wt.% ethanol solution, magnetically stirring at 40 ℃ for 2 minutes until the digoxin is dissolved and clarified to obtain a digoxin solution;

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.9, content: 98.2%, related substances: impurity C0.05%, impurity D not detected, impurity F0.14%, total impurity 1.2%.

Example 6

Prescription: the same as in table 1 of example 1.

The preparation method comprises the following steps:

according to the prescription of Table 1, the medicinal ethanol with the prescription amount is measured, and the water for injection is added to 25.0ml to prepare an ethanol solution with 80 wt%; adding the prescribed amount of digoxin into 80wt.% ethanol solution, stirring for 5 minutes at 40 ℃, and dissolving and clarifying to obtain a digoxin solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, adding 5wt.% of anhydrous disodium hydrogen phosphate solution to adjust the pH value of the solution to 7.5, adding water for injection to the total preparation amount, filtering with a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ under high pressure for 15min to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 7.5, content: 98.4%, related substances: impurity C is not detected, impurity D is not detected, impurity F is 0.13%, and total impurity is 1.2%.

Example 7

Prescription: the same as in table 1 of example 1.

The preparation method comprises the following steps:

according to the prescription of Table 1, the medicinal ethanol with the prescription amount is measured, and the water for injection is added to 25.0ml to prepare an ethanol solution with 80 wt%; adding the prescribed amount of digoxin into an 80wt.% ethanol solution, magnetically stirring for 1 minute at 40 ℃ until the digoxin is dissolved and clarified to obtain a digoxin solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, adding 5wt.% of anhydrous disodium hydrogen phosphate solution to adjust the pH value of the solution to 7.2, adding water for injection to the total preparation amount, filtering with a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ under high pressure for 15min to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 7.2, content: 98.5%, related substances: impurity C0.05%, impurity D not detected, impurity F0.12%, total impurity 1.2%.

Example 8

Prescription:

the compositions and amounts of the digoxin injections shown in Table 1 were as shown in Table 1 except that the amounts of digoxin were adjusted to 0.02g and 0.1 mg/ml.

The preparation method comprises the following steps:

according to the adjusted prescription of the table 1, taking the medicinal ethanol with the prescription amount, adding water for injection to 25.0ml, and preparing 80% ethanol solution; adding the prescribed amount of digoxin into 80% ethanol solution, magnetically stirring for 2 minutes at 40 ℃, dissolving and clarifying to obtain digoxin solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, measuring the pH value to be 6.8, adding water for injection until the total amount is prepared, filtering by using a 0.22 mu m hydrophilic polyvinylidene fluoride filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ under high pressure for 15min to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.8, content: 99.0%, related substances: impurity C is not detected, impurity D is not detected, impurity F is 0.06%, and total impurity is 0.5%.

Example 9

Digoxin injection formulations, see table 2.

Table 2 composition of digoxin injection formulation

Raw and auxiliary materials	Dosage of	Proportion (%)
			Digoxin	0.05g	0.25mg/ml
Medicinal ethanol	21.0ml	10.5
			Propylene glycol	80.0ml	40.0
Monopotassium phosphate	0.30g	0.15
			Sodium hydroxide	Proper amount of	N/A
Water for injection	Added to 200ml (100 pieces)	N/A

The preparation method comprises the following steps:

according to the prescription of Table 2, the medicinal ethanol with the prescription amount is measured, and the water for injection is added to 25.0ml to prepare an ethanol solution with 80 wt%; adding the prescribed amount of digoxin into an 80wt.% ethanol solution, magnetically stirring at 40 ℃ for 2 minutes until the digoxin is dissolved and clarified to obtain a digoxin solution;

adding the potassium dihydrogen phosphate with the prescription amount into 80ml of water for injection, stirring and dissolving at 40 ℃ to obtain a buffer solution, adding the propanediol with the prescription amount, and stirring until the solution is uniformly dissolved to obtain a stabilizer solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, adding 5% sodium hydroxide solution to adjust the pH value to 6.8, adding water for injection to the total preparation amount, filtering by a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ under high pressure for 15min to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.8, content: 98.7%, related substances: impurity C0.05%, impurity D not detected, impurity F0.15%, total impurity 1.3%.

Example 10 Filter compatibility test

The proportion of organic solvent in the digoxin injection is higher than that of a common injection preparation, the content of the organic solvent is about 50%, the commercial production liquid medicine amount is large, the process is longer, the common materials in the field, such as polyethersulfone, are easy to influence the liquid medicine quality, possibly lead to disqualification of relevant substance items of the product, in European pharmacopoeia EP10.5, the sum of impurities is required to be less than or equal to 3.5%, the sum of single unknown impurities is required to be less than or equal to 0.2%, and the sum of impurities except for A, B, C, E, F, G, K and L is required to be less than or equal to 0.7%.

Taking the unfiltered part of the liquid medicine after the injection water is added to the total preparation amount in the example 1, carrying out a filter material compatibility test after the preparation and the central control inspection are qualified (without terminal sterilization), respectively soaking a hydrophilic polytetrafluoroethylene filter membrane, a polyvinylidene fluoride filter membrane and a polyether sulfone filter membrane in the grouped liquid medicine to be tested by taking the unfiltered liquid medicine as a reference, and respectively detecting related substances at 18 hours and 24 hours in consideration of the commercial production process, wherein impurities possibly existing in the digoxin raw material medicine are shown in the table 3:

TABLE 3 list of related substances for digoxin drug substance

The detection method of the related substances of the product is carried out according to the method disclosed in patent application CN 115856167A.

The results of the quality impact of the filters of different materials on the digoxin injection of the present invention are shown in table 4.

TABLE 4 results of the influence of the Filter Membrane on the quality of digoxin injection

As can be seen from the data in Table 4, the polyether sulfone filter membrane has an effect on the quality of the liquid medicine of the product, the leached substance with the content of 0.83% appears after the filter membrane is soaked for 18 hours, the total impurity content is more than 2%, no leached substance is generated after the filter membrane is soaked in the liquid medicine soaked by the fluorine-containing polyvinylidene fluoride and the hydrophilic polytetrafluoroethylene filter membrane for 24 hours, and the total impurity content is less than 1.5%.

Comparative example 1a method for preparing digoxin injection, comprising the following steps:

the prescription is the same as that of the example 1, and the specific preparation method is as follows:

measuring the medicinal ethanol with the prescription dosage, adding water for injection to 25.0ml to prepare 80% ethanol solution, and uniformly mixing with propylene glycol with the prescription dosage;

adding the prescribed amount of digoxin into the mixed solution of ethanol and propylene glycol, and magnetically stirring at 40 ℃ for 60 minutes until the digoxin is dissolved and clarified;

adding anhydrous disodium hydrogen phosphate and citric acid with the prescribed amount into 80ml of water for injection, stirring and dissolving, stirring and mixing with solution containing digoxin uniformly, adding 5% citric acid solution to adjust the pH value of the solution to 6.5, adding water for injection to the total preparation amount, filtering with 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ for 15min to obtain the digoxin injection.

During the formulation, the dissolution of digoxin in example 1 and comparative example 1 was observed and the results are shown in table 5.

TABLE 5 dissolution time of digoxin

According to the method disclosed by the invention, the dissolution rate of the digoxin can be obviously improved by adopting a mode of dissolving the digoxin in an 80% ethanol solution and uniformly mixing the digoxin with other solvents according to the dissolution time of the digoxin in the embodiment 1 and the comparative embodiment 1, so that the commercial production efficiency of the product is improved.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.5, content: 98.4%, related substances: impurity C0.05%, impurity D not detected, impurity F0.12%, total impurity 1.2%.

Comparative example 2

measuring the medicinal ethanol with the prescription dosage, adding water for injection to 25.0ml, and preparing 80% ethanol solution;

pouring the digoxin solution into the uniformly mixed stabilizer solution, uniformly stirring, adding 5% citric acid solution to adjust the pH value of the solution to 6.0, adding water for injection to the total amount, filtering by a 0.22 mu m hydrophilic polytetrafluoroethylene filter membrane, filling and sealing an ampoule, and sterilizing at 121 ℃ under high pressure for 15min to obtain the digoxin injection.

The detection indexes and the results are as follows:

traits: colorless clear liquid, pH: 6.1, content: 98.0%, related substances: impurity C0.05%, impurity D not detected, impurity F0.13%, total impurity 1.3%.

EXAMPLE 11 quality stability study

(1) High temperature 60 DEG C

The digoxin injections of examples 1, 6, 7, 9 and comparative examples 1 to 2 were subjected to high temperature 60℃quality study with the original developer (manufacturer: covis pharma BV, lot number: 7C 261A), and the properties, pH and related substances were examined, and the detection methods of the related substances were carried out according to the methods disclosed in patent application CN115856167A, and the results of the quality stability at 60℃for 10 days are shown in Table 6.

TABLE 6 results of quality studies of different digoxin injections at high temperatures

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Note that: the impurity F content of example 1 in this table is different from that of example 10 in that the impurity F content is lower than that of the liquid medicine after sterilization because the impurity F and the like increase after sterilization, whereas the intermediate solution is not sterilized in example 10.

As can be seen from Table 6, the increase of the relevant substances in comparative examples 1 and 2 is significantly higher than that of examples 1, 6, 7, 9 and the original formulations at a high temperature of 60 ℃, which indicates that the quality of digoxin injection is unstable at lower pH values, such as 6.0-6.5.

(2) Accelerating at 40 ℃ for 6 months

Quality studies of examples 1, 6, 7, 9 and the original preparation (manufacturer: covis phama. Bv, lot No. 8L 268) were conducted under acceleration conditions of 40 ℃ and 75% RH for 6 months, and properties, pH values, contents and related substances were examined, and the method of detecting contents was referred to the method of digoxin injection in united states pharmacopeia USP43, and the results are shown in table 7, wherein the main degradation impurities of the product were impurity C, D, F, and therefore the related substances column only lists the changes of the main degradation impurities and total impurities.

TABLE 7 results of quality studies under different digoxin injectas acceleration tests

Remarks: neglecting the limit: the area of the main peak of the self control solution is 0.05 times (0.05%).

The results in tables 6-7 show that during the test period, the degradation impurity C, impurity D and impurity F of the examples 1, 6, 7 and 9 and the original preparation slightly increase at 60 ℃ and 40 ℃ under the acceleration condition of RH75%, but the total impurity is within the product quality requirement, and the key quality attributes such as the properties, the pH value and the content are not obviously changed, so that the quality of the digoxin injection provided by the invention is consistent with that of the original preparation.

Therefore, the ethanol is prepared into 75-85% ethanol solution for dissolving the digoxin, so that the digoxin can be quickly dissolved within 5 minutes, the generation of extract is avoided, the production time is greatly shortened, and the production efficiency is improved; the pH value of the liquid medicine is controlled to be 6.8-7.5 by adding anhydrous disodium hydrogen phosphate-citric acid buffer solution or potassium dihydrogen phosphate-sodium hydroxide buffer solution, the obtained digoxin injection has good quality stability, and the total impurity of related substances of a finished product preparation is less than 2.0% and the content is more than 97.0% under the acceleration condition of 40 ℃ and RH75% for 6 months.

Claims

1. A preparation method of a digoxin injection with stable quality comprises the following steps:

in the prescription, the content of digoxin is 0.1-0.25 mg/ml, the content of ethanol is 9.0-11.0 vol.%, and the content of propylene glycol is 38.0-42.0 vol.%.

2. The method for preparing a stable quality digoxin injection according to claim 1, characterized in that in step 1), the ethanol content in the ethanol solution is 78-82 wt.%.

3. The method for preparing a stable quality digoxin injection according to claim 1, wherein in the step 2), the buffer is anhydrous disodium hydrogen phosphate-anhydrous citric acid buffer pair or potassium dihydrogen phosphate-sodium hydroxide buffer pair.

4. A method for preparing a stable quality digoxin injection according to claim 3, characterized in that the anhydrous disodium hydrogen phosphate in the buffer is added in its hydrate form and the anhydrous citric acid is added in its hydrate form; or the potassium dihydrogen phosphate is added in the form of its hydrate.

5. The method for preparing the digoxin injection with stable quality according to claim 1, wherein in the step 1), the dissolution temperature of stirring and clearing is 20-70 ℃, and the clearing time is less than 10 minutes.

6. The method for preparing a stable quality digoxin injection according to claim 5, wherein in step 1), the dissolution temperature of stirring solution is 25-40 ℃, and the dissolution time is <5 minutes.

7. The method for preparing a stable quality digoxin injection according to claim 1, wherein in step 2), after the buffer solution is obtained, the prescribed amount of propylene glycol is added into the buffer solution, and the mixture is stirred until the mixture is uniform, so as to prepare a stabilizer solution, and the digoxin solution and the stabilizer solution are mixed.

8. The method for preparing a stable quality digoxin injection according to any one of claims 1-7, characterized in that in step 3), a fluorine-lined filter element or a filter membrane is adopted during filtration.

9. The method for preparing a digoxin injection with stable quality according to claim 8, wherein in the step 3), the filter element is a hydrophilic polytetrafluoroethylene filter element or a polyvinylidene fluoride filter element.

10. The method for preparing a stable quality digoxin injection according to claim 1, wherein in step 3), the sterilization temperature is 121 ℃ and the sterilization time is 15 minutes.