CN106943346B - Methdigoxin liquid preparation, preparation method and application thereof - Google Patents
Methdigoxin liquid preparation, preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to a liquid formulation of digoxin, which comprises digoxin as an active ingredient and arginine and/or histidine or a salt thereof as a stabilizer. The invention also relates to a preparation method and application of the liquid preparation of the meglumine.
Description
Technical Field
The invention relates to a liquid preparation containing methyl digoxin for treating heart failure and arrhythmia, in particular to a methyl digoxin injection and an oral solution, and a preparation method and application thereof.
Background
In 1542, the german scholars Fuchsius created digitalis, a common vocabulary for naming digitalis plants. In 1785, William heating published a work on the pharmacological effects of Digitalis purpurea in the first system. The physician thereafter begins using digoxin preparations to treat edema, cardiac arrhythmias, and Chronic Heart Failure (CHF). The famous DIG test results published in 1997, once again, establish the therapeutic position of digoxin in CHF. To date, digoxin is one of the most commonly used drugs indispensable for relieving symptoms in patients with CHF, and is also a common agent for controlling ventricular rate in patients with Atrial Fibrillation (AF) at rest.
Digoxin is used as a medicine for treating heart failure, the treatment window is narrow, the dosage of digoxin needs to be strictly monitored in clinical application, and the daily dose reaches 0.5-1.25 mg. Methyl digoxin is also a digitonin cardiac glycoside drug, is a digoxin derivative, and has the same effect as digoxin. Because the hydroxyl group of the digitoxin sugar at the tail end of the chemical structure of the digitoxin is methylated, the polarity of the digitoxin sugar is reduced, and the lipophilicity of the digitoxin sugar is correspondingly improved, so the digitoxin sugar has the characteristics of quick and safe absorption, quick effect, strong action, small dosage, long half-life period and the like compared with digoxin which is orally taken. The traditional Chinese medicine composition is mainly used for congestive heart failure and supraventricular tachyarrhythmia clinically, generally, the curative effect of the traditional Chinese medicine composition is better than that of digoxin, and the traditional Chinese medicine composition is particularly suitable for patients who cannot tolerate the digoxin and are safer for patients with heart failure and renal insufficiency.
The liquid preparation of the digoxin is easy to hydrolyze and oxidize and is not easy to stabilize, and the phenomena of low content and increase of related substances can occur in the preparation process and the storage process. Therefore, a stable liquid formulation of digoxin is needed.
Disclosure of Invention
The meglumine liquid is currently available on the market in the form of tablets, oral drops and injections. Methyl digoxin is a glycoside derivative, and the hemiacetal structure on aglycone and the oxygen-glycoside bond of digitoxin glycosyl are very unstable under acidic conditions, so digoxin and digoxigenin which are impurities of digitalis are easily generated in a long-term sample retention process or a process.
Therefore, the invention provides a liquid preparation of digoxin, which adopts arginine and histidine as stabilizing agents, effectively improves the stability of the liquid preparation of digoxin, particularly greatly improves the stability in the sterilization process of a digoxin injection, and reduces the amount of impurities digoxin ligand and digoxin.
The present invention provides a liquid formulation of digoxin, which comprises digoxin as an active ingredient and arginine and/or histidine or a salt thereof as a stabilizer.
In one embodiment, in the liquid formulation of digoxin, the digoxin solution is in a mixed solution of glycerol, propylene glycol, ethanol, and water.
The arginine and the histidine have special amino groups, in a weakly alkaline environment, the guanidyl and the amino groups of the arginine and the amino groups of the histidine are positively charged, and can form hydrogen bonds with carbonyl groups on the digoxin aglycone, and simultaneously carboxyl groups of the two amino acids can form hydrogen bonds with hydroxyl hydrogen protons on the digoxin aglycone due to the negative charge, so that the stability of the digoxin in the weakly alkaline environment is improved, as shown in figure 1.
In the present invention, the concentration of digoxin as an active ingredient is between 0.01mg/ml and 10 mg/ml. The liquid preparation of digoxin of the invention comprises oral liquid preparation and injection of digoxin. In the case of oral liquid preparations, the oral liquid preparation may be drops with a high concentration of digoxin between 0.6mg/ml and 10mg/ml, or may be an oral solution with a low concentration of digoxin between 0.01mg/ml and 0.1 mg/ml. In the case of an injection, the concentration of digoxin is between 0.01mg/ml and 0.6 mg/ml.
The concentration of arginine and/or histidine or a salt thereof as a stabilizer of the present invention is related to the concentration of the main drug digoxin. That is, the higher the concentration of digoxin, the higher the concentration of arginine and/or histidine or salts thereof required. And arginine and/or histidine or salts thereof at high concentrations in amounts that stabilize low concentrations of digoxin. In some embodiments, the liquid formulation of digoxin of the present invention may have a mass ratio of digoxin to stabilizer ranging from 0.01 to 1, or from 0.02 to 1. In some embodiments, the mass ratio of methyl digoxin to stabilizer may range from 0.06 to 1. In some embodiments, the mass ratio of methyl digoxin to stabilizer may range from 0.08 to 1. In some embodiments, the mass ratio of methyl digoxin to stabilizer may range from 0.1 to 1. In some embodiments, the mass ratio of meglumine to stabilizer may be 0.01, 0.015, 0.017, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.
In the present invention, arginine and histidine or salts thereof may be used alone or in combination at an arbitrary ratio, and the stability of the pharmaceutical solution of digoxin can be greatly improved. If the two are used in combination in any ratio, such as arginine and histidine, the concentration of arginine and histidine is the concentration in the liquid formulation after mixing.
In one embodiment, the arginine or salt thereof is used alone at a concentration of 0.01mg/ml to 100 mg/ml. In particular, the arginine or salt thereof is preferably at a concentration of 10mg/ml to 100mg/ml, particularly preferably 35mg/ml to 70mg/ml, most preferably 40mg/ml to 65mg/ml, in particular 10mg/ml, 20mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 50mg/ml, 60mg/ml, 65mg/ml, 70mg/ml, 80mg/ml, 90mg/ml or 100mg/ml, when preparing drops. In the preparation of an oral solution, the arginine or a salt thereof is preferably at a concentration of 0.1mg/ml to 10mg/ml, particularly preferably 0.3mg/ml to 1.0mg/ml, most preferably 0.4mg/ml to 0.6mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10 mg/ml. In the preparation of an injection, the arginine or a salt thereof is preferably at a concentration of 0.1mg/ml to 10mg/ml, particularly preferably 0.4mg/ml to 2.0mg/ml, most preferably 0.8mg/ml to 1.0mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10 mg/ml.
In one embodiment, the histidine or salt thereof is used alone at a concentration of 0.01mg/ml to 100 mg/ml. In particular, the concentration of histidine or a salt thereof is preferably from 10mg/ml to 100mg/ml, especially preferably from 35mg/ml to 70mg/ml, most preferably from 40mg/ml to 65mg/ml, in particular 10mg/ml, 20mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 50mg/ml, 60mg/ml, 65mg/ml, 70mg/ml, 80mg/ml, 90mg/ml or 100mg/ml, when preparing drops. The concentration of histidine or a salt thereof is preferably 0.1mg/ml to 10mg/ml, particularly preferably 0.3mg/ml to 1.0mg/ml, most preferably 0.4mg/ml to 0.6mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10mg/ml, when preparing an oral solution. The concentration of histidine or a salt thereof is preferably 0.1mg/ml to 10mg/ml, particularly preferably 0.4mg/ml to 2.0mg/ml, most preferably 0.8mg/ml to 1.0mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10mg/ml, when preparing an injection.
In one embodiment, arginine and histidine are used in combination, and the total concentration of arginine and histidine in the liquid formulation is 0.01mg to 100 mg/ml. In particular, in the preparation of drops, the arginine and histidine or salts thereof are preferably present in the drops in a total concentration of from 10mg/ml to 100mg/ml, particularly preferably of from 35mg/ml to 70mg/ml, most preferably of from 40mg/ml to 65mg/ml, in particular of from 10mg/ml, 20mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 50mg/ml, 60mg/ml, 65mg/ml, 70mg/ml, 80mg/ml, 90mg/ml or 100 mg/ml. In the preparation of an oral solution, the total concentration of the arginine and histidine or salts thereof in the oral solution is preferably 0.1mg/ml to 10mg/ml, particularly preferably 0.3mg/ml to 1.0mg/ml, most preferably 0.4mg/ml to 0.6mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10 mg/ml. In preparing an injection, the total concentration of the arginine and histidine or salts thereof in the injection is preferably 0.1mg/ml to 10mg/ml, particularly preferably 0.4mg/ml to 2.0mg/ml, most preferably 0.8mg/ml to 1.0mg/ml, specifically 0.1mg/ml, 0.2mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1.0mg/ml, 2.0mg/ml, 3.0mg/ml, 4.0mg/ml, 5.0mg/ml, 6.0mg/ml, 7.0mg/ml, 8.0mg/ml, 9.0mg/ml or 10 mg/ml.
In one embodiment, the liquid formulation of the present invention employs a mixed vehicle including, but not limited to, a mixture of ethanol, propylene glycol, glycerol and water.
The solvent for preparing the methyl digoxin is a common solvent in pharmacy, and is of a medicinal grade. The following common solvents account for the volume percentage (V/V) of the total volume of the preparation: the specific proportion is calculated according to the volume ratio: the ethanol content is 3-20%, preferably 3-15%, particularly preferably 5-10%, and most preferably 6-8%; 10-40% of propylene glycol, preferably 15-35%, particularly preferably 20-30%, and most preferably 25-30%; the content of the glycerol is 30-50%, preferably 30-45%, particularly preferably 35-45%, and most preferably 40-45%; the amount of water is 10 to 20%, preferably 10 to 18%, particularly preferably 12 to 16%, most preferably 14 to 15%.
In one embodiment, in the case where the liquid preparation of the present invention is a digoxin injection, the injection further contains sodium chloride as an osmotic pressure regulator, wherein the amount of sodium chloride is 20mg/L to 9000mg/L, preferably 40mg/ml to 4000mg/ml, particularly preferably 160mg/ml to 800mg/ml, and most preferably 320mg/ml to 400 mg/ml.
In the invention, the methyl digoxin exists in a dissolved state in all formula compositions and mixed solvents, and experiments prove that the methyl digoxin has better stability as a main medicine when the pH value of a liquid medicine containing the methyl digoxin ranges from 6.0 to 8.0. Especially, the stability is better when the pH value is 7.0-8.0.
The present invention also provides a method for preparing a liquid formulation of digoxin, comprising formulating a solution containing digoxin as an active ingredient and arginine and/or histidine or a salt thereof as a stabilizer.
In one embodiment, in the case where the liquid formulation of digoxin is oral drops of digoxin, the method of preparation is:
adding the digoxin into the ethanol with the prescription amount, stirring and dissolving, sequentially adding the digoxin into the solution of the glycerol, the propylene glycol and the water with the prescription amount, stirring for 1 hour, and filtering. And adding a stabilizer into the solution, and adjusting the pH of the liquid medicine to 7.0-8.0 by using a pH regulator. Filtering the medicinal liquid, and packaging.
In one embodiment, in the case that the liquid formulation of digoxin is a digoxin oral solution, the preparation method is:
adding a methyl digoxin raw material and a stabilizer into a mixed solvent of glycerol, propylene glycol, water and ethanol in a formula amount, stirring for 1h, filtering, and adjusting the pH of the liquid medicine to 7.0-8.0 by using a pH regulator. Filtering the medicinal liquid, and packaging.
In one embodiment, in the case that the liquid formulation of digoxin is a digoxin injection, the preparation method comprises:
adding digoxin into ethanol, stirring for dissolving, sequentially adding glycerol, propylene glycol, water and sodium chloride, sealing, heating to 60 deg.C, adding activated carbon, stirring for 1h, and filtering. Adding the stabilizer into the solution, stirring to dissolve, and keeping at 60 ℃. And adjusting the pH of the liquid medicine to 7.0-8.0 by using a pH regulator. Filtering the medicinal liquid with 0.22um microporous membrane. Filling, the filled sample is placed in a sterilization cabinet, and the sterilization is carried out for 30 minutes at 100 ℃.
The pH adjusting agent used in the present invention is an alkaline inorganic or organic salt, sodium or potassium salt, including but not limited to sodium hydroxide, dipotassium hydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, sodium citrate, or sodium malate. Preferably sodium hydroxide solution, the concentration of which is 0.1 mol/L.
The liquid preparation of meglumine of the invention can also comprise further pharmaceutically acceptable carriers and/or adjuvants according to specific needs. The type, use, and amount of the pharmaceutically acceptable carrier and/or adjuvant are conventional in the art and are well known to those of ordinary skill in the art.
The liquid preparation of the digoxin provided by the invention adopts packaging materials including, but not limited to, polyester plastic bottles, polyethylene plastic bottles, calcium sodium glass bottles, low borosilicate glass bottles and the like.
The invention has the beneficial effects that:
the existing medigoxin preparations on the market at home only comprise a medigoxin tablet preparation, have single dosage form, and can not meet the requirements of clinical treatment, such as children and old patients with dysphagia. In addition, as the digoxin is taken as a derivative of digoxin, the polarity of digoxin is reduced due to the methylation of the hydroxyl group of digoxin sugar at the tail end of the chemical structure, and the lipophilicity of the digoxin sugar is correspondingly improved, so that the digoxin derivative is quicker and safer to absorb than the digoxin after being orally taken, and has the characteristics of quick response, strong action, small dosage, long half-life period and the like. The liquid preparation of the digoxin has the defects of easy hydrolysis and oxidation and difficult stability, and the phenomena of low content and increase of related substances can occur in the preparation process and the storage process. The invention effectively improves the stability of the digoxin liquid preparation and solves the problem that the digoxin liquid preparation cannot be stably stored by adding the stabilizer in the preparation process.
Drawings
Figure 1 shows the stabilizing effect of arginine on digoxin.
Detailed Description
The following examples merely provide further illustrations of the preparation of the formulations and compositions of the present invention. The scope of the present invention should not be construed as being limited to the following examples.
Example 1
Preparation of meglumine oral drops
Composition of meglumine oral drops
Adding water to 1000ml, and making into 100 pieces. Wherein the concentration of arginine is 35 mg/ml.
Adding the raw material of the methyl digoxin into ethanol, stirring for dissolving, sequentially adding the glycerol, the propylene glycol and the water with the prescription amount, heating the obtained solution to 60 ℃, stirring for 1 hour, and filtering. Adding arginine in a prescription amount into the solution, and adjusting the pH value of the liquid medicine to 7.0-8.0 by using 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 2
Preparation of meglumine oral drops
Composition of meglumine oral drops
Adding water to 1000ml, and making into 100 pieces. Wherein the concentration of arginine is 50 mg/ml.
Adding the raw material of the methyl digoxin into ethanol, stirring for dissolving, sequentially adding the glycerol, the propylene glycol and the water with the prescription amount, heating the obtained solution to 60 ℃, stirring for 1 hour, and filtering. Adding arginine in a prescription amount into the solution, and adjusting the pH value of the liquid medicine to 7.0-8.0 by using 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 3
Preparation of meglumine oral drops
Composition of meglumine oral drops
Adding water to 1000ml, and making into 100 pieces. Wherein arginine is present at a concentration of 20mg/ml, histidine is present at a concentration of 40mg/ml, and the combination of arginine and histidine is present at a concentration of 60 mg/ml.
Adding the raw material of the methyl digoxin into ethanol, stirring for dissolving, sequentially adding the glycerol, the propylene glycol and the water with the prescription amount, heating the obtained solution to 60 ℃, stirring for 1 hour, and filtering. Adding arginine and histidine in a prescription amount into the solution, and adjusting the pH value of the liquid medicine to 6.0-8.0 by using 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 4
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein the concentration of arginine is 5 mg/ml.
Adding methyl digoxin raw material and arginine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1h, filtering, and adjusting pH of the liquid medicine to 7.2 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 5
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein the concentration of histidine is 1.0 mg/ml.
Adding digoxin raw material and histidine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1 hr, filtering, and adjusting pH of the medicinal liquid to 6.8 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 6
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein arginine is present at a concentration of 1.5mg/ml, histidine is present at a concentration of 1.5mg/ml, and the total concentration of the combination of both is 3 mg/ml.
Adding digoxin raw material, histidine and arginine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1 hr, filtering, and adjusting pH of the medicinal liquid to 7.4 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 7
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein the concentration of arginine is 0.01 mg/ml.
Adding methyl digoxin raw material and arginine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1h, filtering, and adjusting pH of the liquid medicine to 7.2 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 8
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein the concentration of histidine is 0.01 mg/ml.
Adding digoxin raw material and histidine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1 hr, filtering, and adjusting pH of the medicinal liquid to 6.8 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 9
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein arginine is 0.005mg/ml, histidine is 0.005mg/ml, and the combination of both is 0.01 mg/ml.
Adding digoxin raw material, histidine and arginine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1 hr, filtering, and adjusting pH of the medicinal liquid to 7.4 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Example 10
Preparation of meglumine injection
Composition of methyl digoxin injection
Adding water for injection to 200ml, and making into 100 pieces. Wherein the concentration of arginine is 0.5 mg/ml. Adding ethanol into the solution of glycerol, propylene glycol and water, sealing, heating to 60 deg.C, adding arginine and active carbon, stirring for 1 hr, and filtering. The raw material of methyl digoxin and sodium chloride are added into the solution, stirred and dissolved, and the temperature is kept at 60 ℃. The pH of the solution was adjusted to pH7.4 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid with 0.22um microporous membrane, bottling, and sealing (under sterile condition).
Example 11
Preparation of meglumine injection
Composition of methyl digoxin injection
Adding water for injection to 200ml, and making into 100 pieces. Wherein the concentration of histidine is 0.15 mg/ml.
Adding ethanol into solution of glycerol, propylene glycol and water, sealing, heating to 60 deg.C, adding histidine, stirring with activated carbon for 1 hr, and filtering. The raw material of methyl digoxin and sodium chloride are added into the solution, stirred and dissolved, and the temperature is kept at 60 ℃. The pH of the solution was adjusted to pH7.6 by 0.1mol/L sodium hydroxide solution, and the solution was maintained at 60 ℃. Filtering the medicinal liquid with 0.22um microporous membrane. And (4) filling, namely placing the filled sample in a sterilization cabinet, and sterilizing for 30 minutes at 100 ℃.
Example 12
Preparation of meglumine injection
Composition of methyl digoxin injection
Adding water for injection to 200ml, and making into 100 pieces. Wherein arginine is present at a concentration of 0.6mg/ml, histidine is present at a concentration of 0.4mg/ml, and a combined concentration of 1.0mg/ml is used.
Adding ethanol into the solution of glycerol, propylene glycol and water, sealing, heating to 60 deg.C, adding arginine and histidine, stirring with activated carbon for 1 hr, and filtering. The raw material of methyl digoxin and sodium chloride are added into the solution, stirred and dissolved, and the temperature is kept at 60 ℃. The pH of the solution was adjusted to pH7.6 by 0.1mol/L sodium hydroxide solution, and the solution was maintained at 60 ℃. Filtering the medicinal liquid with 0.22um microporous membrane. Filling, the filled sample is placed in a sterilization cabinet, and the sterilization is carried out for 30 minutes at 100 ℃.
Comparative example 1
In the composition of example 1, arginine as a stabilizer was not added, and the other composition was not changed.
Preparation of meglumine oral drops
Composition of meglumine oral drops
Adding water to 1000ml, and making into 100 pieces.
Adding the raw material of the methyl digoxin into ethanol, stirring for dissolving, sequentially adding the glycerol, the propylene glycol and the water with the prescription amount, heating the obtained solution to 60 ℃, stirring for 1 hour, and filtering. And adjusting the pH value of the liquid medicine to 7.0-8.0 by using 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Comparative example 2
The composition of example 4 was made with a reduced amount of arginine as a stabilizer, and the others were unchanged.
Preparation of an oral solution of meglumine
Composition of oral solution of methyl digoxin
Adding water to 1000ml, and making into 100 bottles. Wherein the concentration of arginine is 0.005 mg/ml.
Adding methyl digoxin raw material and arginine into mixed solvent of glycerol, propylene glycol, water and ethanol, stirring for 1h, filtering, and adjusting pH of the liquid medicine to 7.2 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid, and packaging.
Comparative example 3
The composition of example 10 was made without the addition of arginine as a stabilizer, and the rest were unchanged.
Preparation of meglumine injection
Composition of methyl digoxin injection
Adding water for injection to 200ml, and making into 100 pieces.
Adding ethanol into solution of glycerol, propylene glycol and water, sealing, heating to 60 deg.C, stirring with activated carbon for 1 hr, and filtering. The raw material of methyl digoxin and sodium chloride are added into the solution, stirred and dissolved, and the temperature is kept at 60 ℃. The pH of the solution was adjusted to pH7.4 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid with 0.22um microporous membrane, bottling, and sealing (under sterile condition).
Comparative example 4
A small amount of the stabilizer arginine was added to the composition of example 10, and the rest was unchanged.
Preparation of meglumine injection
Composition of methyl digoxin injection
Adding water for injection to 200ml, and making into 100 pieces. Wherein the concentration of arginine is 0.005 mg/ml.
Adding ethanol into the solution of glycerol, propylene glycol and water, sealing, heating to 60 deg.C, adding arginine and active carbon, stirring for 1 hr, and filtering. The raw material of methyl digoxin and sodium chloride are added into the solution, stirred and dissolved, and the temperature is kept at 60 ℃. The pH of the solution was adjusted to pH7.4 with 0.1mol/L sodium hydroxide solution. Filtering the medicinal liquid with 0.22um microporous membrane, bottling, and sealing (under sterile condition).
Example 13
Comparison of stability findings
A stability test investigation method according to the guidelines of stability tests of raw materials and preparations (2015 pharmacopoeia):
test samples: examples 1 to 12 and comparative examples 1 to 3
The placing conditions are as follows: 40 +/-2 ℃ and 25 +/-5% RH
Investigation time: 0 day for 6 months
The project is examined for specific impurities (digoxin, digoxigenin, α -methyl digoxin), other maximum single impurities and total impurities.
Comparative results of the materials of the formulation of the examples of the present invention and the comparative examples
TABLE 1 comparison of the stability of the liquid formulations of meglumine of examples 1-12 with that of comparative examples 1-3
It can be seen that by adopting the formula of the embodiment of the invention, the liquid preparation is accelerated for 6 months, the impurity change is small obviously, particularly the total impurities, digoxin, digoxigenin and other maximum single impurities are increased by 20% of the reference liquid preparation added with a small amount of stabilizer or without the stabilizer, and the stability is improved obviously.
Example 14
Investigation of Sterilization stability
The sterilization stability was investigated according to the moist heat sterilization method in the general rule "sterilization method" in the four parts of the pharmacopoeia 2015 edition.
Test samples: examples 10 to 12 and comparative examples 3 and 4
The placing conditions are as follows: sterilizing at 121 deg.C for 15 min
Investigation time: 0 day after sterilization
And (4) investigating items: specific impurities (digoxin, digoxigenin, digitoxin) and total impurities.
For the examination of sterilization stability, the results of the related substances of the formulation of the injection liquid in the example and the comparative example are compared.
TABLE 2 comparison of results of sterilization stability of the meglumine injection solutions of examples 10-12 and comparative examples 3-4
After sterilization at 121 ℃ for 15 minutes, the related substances of the formulations of the comparative examples were greatly increased, while the change of impurities of the formulations of the examples of the present invention was remarkably small.
The invention is not limited by the embodiments shown and described above, but may be varied within the scope of the claims.
Claims (12)
1. Liquid formulation of digoxin, characterized by comprising digoxin as an active ingredient and arginine and/or histidine as a stabilizer;
wherein the concentration of the arginine is 0.01mg/ml to 100 mg/ml;
the concentration of the histidine is 0.01mg/ml to 100 mg/ml; and
wherein the pH value of the liquid preparation is between 6 and 8, and
the mass ratio of the methyl digoxin to the stabilizer is 0.01-1.
2. The liquid formulation of digoxin according to claim 1, wherein arginine and histidine are used alone or in combination in any ratio.
3. The liquid formulation of digoxin according to claim 1, wherein the pH of the liquid formulation is between 7 and 8.
4. The liquid formulation of meglumine according to claim 1, wherein the mass ratio of the meglumine to the stabilizer is in the range of 0.017 to 1.
5. The liquid formulation of digoxin according to claim 1, wherein the mass ratio of digoxin to stabilizer ranges from 0.02 to 1.
6. The liquid formulation of digoxin according to claim 1, wherein the mass ratio of digoxin to stabilizer ranges from 0.04 to 1.
7. The liquid formulation of digoxin according to any one of claims 1-6, wherein the content of digoxin is between 0.01mg/ml and 10 mg/ml.
8. The liquid formulation of digoxin according to any one of claims 1-6, further comprising ethanol, water, glycerol, and propylene glycol as a mixed vehicle, wherein each vehicle comprises, in volume percent based on the total volume of the liquid formulation: 3-20% of ethanol, 10-40% of propylene glycol, 30-50% of glycerol and 10-20% of water.
9. The liquid formulation of digoxin according to any one of claims 1-6, wherein the liquid formulation is an oral liquid formulation or an injection solution.
10. The liquid formulation of digoxin according to claim 9, wherein the oral liquid formulation is an oral drop or an oral solution.
11. A method of preparing a liquid formulation of digoxin as set forth in any one of claims 1-10, comprising formulating a solution containing digoxin as an active ingredient and arginine and/or histidine as a stabilizer.
12. Use of a liquid formulation of methacin as claimed in any one of claims 1 to 10 in the manufacture of a medicament for the treatment of heart failure and arrhythmia.
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