An azithromycin composition for injection and a preparation process thereof

Abstract

The application provides an azithromycin composition for injection and a preparation process thereof, and relates to the field of pharmaceutical preparations.The azithromycin composition for injection provided by the application is composed of azithromycin, citric acid and sodium hydroxide.The preparation process comprises the following steps: dissolving azithromycin, citric acid and sodium hydroxide in water for injection to obtain a medicinal solution; and vacuum freeze-drying the medicinal solution to obtain the azithromycin composition for injection; the vacuum freeze-drying process comprises the following steps in sequence: pre-freezing, sublimation drying and desorption drying; the application has the advantages that the prescription and accessories are few in types, the dosages are reasonable, the liquid preparation process is more optimal, the raw material dissolving time is short, the medicinal solution is stable, and no impurities are brought in by using activated carbon; the freeze-drying process cycle is short, the appearance of the freeze-dried product is beautiful, the re-dissolving time is short, the re-dissolved solution is more optimal in clarity, and the freeze-dried product has excellent stability, so that the clinical drug safety of the product is fundamentally ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular, to an azithromycin composition for injection and a preparation process thereof. BACKGROUND

[0002] Azithromycin is a macrolide antibiotic with the advantages of broad antibacterial spectrum and long half-life. Azithromycin for injection is clinically used for treating infections caused by sensitive pathogenic strains, such as community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus or Streptococcus pneumoniae, which requires intravenous drip treatment first; pelvic inflammation caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, which requires intravenous drip treatment first. Azithromycin for injection is marketed in many countries.

[0003] Azithromycin is almost insoluble in water, and its solubility increases in acidic aqueous solution but its stability is poor. In order to increase the solubility and stability of the raw material, the freeze-drying formability, the existing technology generally adds citric acid to increase the solubility of the raw material and the stability of the liquid medicine, and adds excipients (such as mannitol) to increase the formability and stability of the freeze-dried product.

[0004] The inventors found during the research and development that the use of excipients increases the amount of excipients, increases the economic cost, makes the freeze-dried content dense, prolongs the freeze-drying cycle, and the reconstituted solution has poor clarity, and the interaction between the raw and auxiliary materials during long-term storage easily damages the safety of the drug for clinical use. Therefore, it is extremely important and urgent to develop an azithromycin for injection freeze-dried preparation with less types of excipients, short raw material dissolution time and stable liquid medicine, short freeze-drying cycle, stable quality of freeze-dried products and high safety, and a preparation process thereof. SUMMARY

[0005] The purpose of the present application is to develop an azithromycin for injection freeze-dried preparation with less types of excipients, short raw material dissolution time and stable liquid medicine, short freeze-drying cycle, stable quality of freeze-dried products and high safety, and a preparation process thereof.

[0006] The technical solution adopted by the present application is as follows:

[0007] An azithromycin composition for injection, which is composed of azithromycin, citric acid and sodium hydroxide in a mass ratio of 1:(0.825-0.910):(0.34-0.38).

[0008] A preparation process of an azithromycin composition for injection, comprising the following steps: dissolving azithromycin, citric acid and sodium hydroxide in water for injection respectively to obtain a liquid medicine; vacuum freeze-drying the liquid medicine to obtain the azithromycin composition for injection; the vacuum freeze-drying process comprises pre-freezing, sublimation drying and desorption drying in sequence; wherein the pre-freezing is 5℃ for 40-60 min; cooling to -45 to -40℃ for 30 min and keeping for 120-150 min.

[0009] Further, the sublimation drying is 30 min for heating to -20 to -30℃, keeping for 120-150 min, and vacuum degree 0.2 mbar; 30 min for heating to -5 to 0℃, keeping for 1200 min, and vacuum degree 0.2 mbar.

[0010] Further, the pre-freezing is 5℃ for 60 min; 30 min for cooling to -45℃, keeping for 150 min.

[0011] Further, the sublimation drying is 30 min for heating to -20 to -30℃, keeping for 120 min, and vacuum degree 0.2 mbar; and then 30 min for heating to -5℃, keeping for 1200 min, and vacuum degree 0.2 mbar.

[0012] Further, the desorption drying is 20 min for heating to 10℃, keeping for 100 min, and vacuum degree 0.2 mbar; 20 min for heating to 30 to 40℃, keeping for 350 min, and vacuum degree 0.1 mbar.

[0013] Further, the pH value of the liquid medicine is 6.4-6.8.

[0014] Further, the liquid medicine is prepared by the following method:

[0015] Adding 26%-29% of the prescription amount of citric acid in 40%-60% of water for injection, dissolving, adding the prescription amount of azithromycin, dissolving to obtain a first solution;

[0016] Adding the remaining prescription amount of citric acid in 15%-30% of water for injection, dissolving, adding the prescription amount of sodium hydroxide, dissolving to obtain a second solution;

[0017] Mixing the second solution into the first solution, adding water for injection to the total amount, stirring uniformly, and filtering to obtain the liquid medicine.

[0018] The application provides an azithromycin composition for injection and a preparation process thereof, wherein the prescription auxiliary material is less in variety, the usage is reasonable, the solution preparation process is more optimal, the raw material dissolution time is short, the solution is stable, and no impurities are brought by activated carbon. The freeze-drying process is short, the appearance of the obtained freeze-dried product is beautiful, the reconstitution time is short, the reconstitution solution is more optimal in clarity, and the product has excellent stability, thereby fundamentally ensuring the clinical medication safety of the product. DETAILED DESCRIPTION

[0019] Example 1

[0020] The inventor found in the research process that different solution preparation methods have great influences on the dissolution time of API and the stability of the solution. The influences of different solution preparation methods are investigated in this example to screen the optimal solution preparation method. In this example, the prescriptions of all the solution preparation methods are the same, as shown in Table 1.

[0021] Table 1 Prescription composition in Example 1

[0022] Ingredient Amount Azithromycin 10g Citric acid 8.60g Sodium hydroxide 3.55g Water to 100ml

[0023] Solution preparation method 1

[0024] Step 1: 60% of the total prescription preparation amount of water for injection is measured into container A; 25% of the prescription amount of citric acid is added and stirred to dissolve, then the prescription amount of azithromycin is added and stirred to dissolve, to obtain a first solution.

[0025] Step 2: 20% of the total prescription preparation amount of water for injection is measured into container B; the remaining 75% of the prescription amount of citric acid is added and stirred to dissolve, then the prescription amount of sodium hydroxide is added and stirred to dissolve, to obtain a second solution.

[0026] Step 3: The second solution is added to the first solution for mixing, and water for injection is added to the total preparation amount, and then stirred uniformly and filtered to obtain a solution.

[0027] Solution preparation method 2

[0028] Step 1: 60% of the total prescription preparation amount of water for injection is measured into container A; 26% of the prescription amount of citric acid is added and stirred to dissolve, then the prescription amount of azithromycin is added and stirred to dissolve, to obtain a first solution.

[0029] Step 2: 20% of the total prescription preparation amount of water for injection is measured into container B; the remaining 74% of the prescription amount of citric acid is added and stirred to dissolve, then the prescription amount of sodium hydroxide is added and stirred to dissolve, to obtain a second solution.

[0030] Step 3: The second solution is added to the first solution for mixing, and water for injection is added to the total preparation amount, and then stirred uniformly and filtered to obtain a solution.

[0031] Solution preparation method 3

[0032] Step 1: Measure 60% of the total prescription amount of water for injection into container A; add 27% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of azithromycin and stir to dissolve, to obtain a first solution.

[0033] Step 2: Measure 20% of the total prescription amount of water for injection into container B; add the remaining 73% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of sodium hydroxide and stir to dissolve, to obtain a second solution.

[0034] Step 3: Mix the second solution into the first solution, add water for injection to the total prescription amount, stir until uniform, and filter to obtain the medicinal solution.

[0035] Preparation method 4

[0036] Step 1: Measure 60% of the total prescription amount of water for injection into container A; add 28% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of azithromycin and stir to dissolve, to obtain a first solution.

[0037] Step 2: Measure 20% of the total prescription amount of water for injection into container B; add the remaining 72% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of sodium hydroxide and stir to dissolve, to obtain a second solution.

[0038] Step 3: Mix the second solution into the first solution, add water for injection to the total prescription amount, stir until uniform, and filter to obtain the medicinal solution.

[0039] Preparation method 5

[0040] Step 1: Measure 60% of the total prescription amount of water for injection into container A; add 29% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of azithromycin and stir to dissolve, to obtain a first solution.

[0041] Step 2: Measure 20% of the total prescription amount of water for injection into container B; add the remaining 71% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of sodium hydroxide and stir to dissolve, to obtain a second solution.

[0042] Step 3: Mix the second solution into the first solution, add water for injection to the total prescription amount, stir until uniform, and filter to obtain the medicinal solution.

[0043] Preparation method 6

[0044] Step 1: Measure 60% of the total prescription amount of water for injection into container A; add 30% of the prescription amount of citric acid and stir to dissolve, then add the prescription amount of azithromycin and stir to dissolve, to obtain a first solution.

[0045] Step 2: Measure 20% of the total amount of water for injection in container B; add the remaining 70% of the prescribed amount of citric acid and stir to dissolve, then add the prescribed amount of sodium hydroxide and stir to dissolve, to obtain a second solution.

[0046] Step 3: Mix the second solution into the first solution, add water for injection to the total amount, stir until uniform, and filter to obtain the liquid medicine.

[0047] Liquid preparation method 7

[0048] Measure 80% of the total amount of water for injection in a container; first add the prescribed amount of citric acid and stir to dissolve, then add the prescribed amount of sodium hydroxide and stir to dissolve, and finally add the prescribed amount of azithromycin and stir to dissolve; add water for injection to the total amount, stir until uniform, and filter to obtain the liquid medicine.

[0049] Prepare the liquid according to the above liquid preparation methods, and the azithromycin dissolution time and the properties of the obtained liquid medicine are shown in Table 2.

[0050] Table 2: Effects of different liquid preparation methods

[0051] Dispensing method Azithromycin dissolution time (min) Whether the raw material precipitates Liquid pH Method 1 30 No 6.57 Method 2 20 No 6.54 Method 3 18 No 6.56 Method 4 17 No 6.55 Method 5 15 No 6.54 Method 6 15 Yes 6.55 Method 7 60 No 6.58

[0052] As shown in Table 2, according to liquid preparation methods 2-5, the azithromycin dissolution time is short, and the azithromycin does not precipitate during the preparation process, which is suitable for preparing azithromycin for injection.

[0053] Example 2

[0054] The present embodiment provides a preparation process for azithromycin for injection, comprising the following steps:

[0055] Step 1: Prepare the liquid according to the liquid preparation method in Example 1.

[0056] Step 2: Pre-freeze the liquid medicine at 5°C for 60 min, then cool it to -40°C for 30 min and maintain it at -40°C for 150 min.

[0057] Step 3: Sublimation drying, warm the pre-frozen sample to -25°C for 30 min, maintain it at -25°C for 150 min, and the vacuum degree is 0.2 mbar; then warm it to 0°C for 30 min, maintain it at 0°C for 1200 min, and the vacuum degree is 0.2 mbar.

[0058]

[0059] Step 4: Desublimation drying, warm the sublimation-dried sample to 10°C for 20 min, maintain it at 10°C for 100 min, and the vacuum degree is 0.2 mbar; then warm it to 30°C for 20 min, maintain it at 30°C for 350 min, and the vacuum degree is 0.1 mbar; and the process is completed.

[0060] ​The properties of the azithromycin composition for injection obtained in this example are shown in Table 3.

[0061] Example 3

[0062] This example provides a preparation process of an azithromycin composition for injection, comprising the following steps:

[0063] Step 1: The drug solution was prepared according to the preparation method in Example 1.

[0064] Step 2: Pre-freezing, the drug solution was kept at 5°C for 60 min, then cooled to -45°C for 30 min and kept for 120 min.

[0065] Step 3: Sublimation drying, the pre-frozen sample was warmed to -30°C for 30 min, kept for 120 min, and the vacuum degree was 0.2 mbar; then warmed to -5°C for 30 min, kept for 1200 min, and the vacuum degree was 0.2 mbar.

[0066] Step 4: Desorption drying, the sublimation-dried sample was warmed to 10°C for 20 min, kept for 100 min, and the vacuum degree was 0.2 mbar; then warmed to 35°C for 20 min, kept for 350 min, and the vacuum degree was 0.1 mbar; and the product was obtained.

[0067] The properties of the azithromycin composition for injection obtained in this example are shown in Table 3.

[0068] Example 4

[0069] This example provides a preparation process of an azithromycin composition for injection, comprising the following steps:

[0070] Step 1: The drug solution was prepared according to the preparation method in Example 1.

[0071] Step 2: Pre-freezing, the drug solution was kept at 5°C for 60 min, then cooled to -45°C for 30 min and kept for 150 min.

[0072] Step 3: Sublimation drying, the pre-frozen sample was warmed to -20°C for 30 min, kept for 120 min, and the vacuum degree was 0.2 mbar; then warmed to -5°C for 30 min, kept for 1200 min, and the vacuum degree was 0.2 mbar.

[0073] Step 4: Desorption drying, the sublimation-dried sample was warmed to 10°C for 20 min, kept for 100 min, and the vacuum degree was 0.2 mbar; then warmed to 40°C for 20 min, kept for 350 min, and the vacuum degree was 0.1 mbar; and the product was obtained.

[0074] The properties of the azithromycin composition for injection obtained in this example are shown in Table 3.

[0075] Comparative Example 1

[0076] This comparative example provides a preparation process of an azithromycin composition for injection, comprising the following steps:

[0077] Step 1: The drug solution was prepared according to the preparation method in Example 1.

[0078] Step 2: Pre-freezing, the drug solution was cooled to -45°C in 120 min and maintained for 150 min.

[0079] Step 3: Sublimation drying, the pre-frozen sample was warmed to -25°C in 30 min, maintained for 120 min, and the vacuum degree was 0.2 mbar; then warmed to -5°C in 30 min, maintained for 1200 min, and the vacuum degree was 0.2 mbar.

[0080] Step 4: Desorption drying, the sublimation-dried sample was warmed to 10°C in 20 min, maintained for 100 min, and the vacuum degree was 0.2 mbar; then warmed to 35°C in 20 min, maintained for 350 min, and the vacuum degree was 0.1 mbar; and the product was obtained.

[0081] The properties of the azithromycin composition for injection obtained in this example are shown in Table 3.

[0082] Comparative Example 2

[0083] This comparative example provides a preparation process of an azithromycin composition for injection, comprising the following steps:

[0084] Step 1: The drug solution was prepared according to the preparation method in Example 1.

[0085] Step 2: Pre-freezing, the drug solution was cooled to -45°C in 10 min and maintained for 150 min.

[0086] Step 3: Sublimation drying, the pre-frozen sample was warmed to -25°C in 30 min, maintained for 120 min, and the vacuum degree was 0.2 mbar; then warmed to -5°C in 30 min, maintained for 1200 min, and the vacuum degree was 0.2 mbar.

[0087] Step 4: Desorption drying, the sublimation-dried sample was warmed to 10°C in 20 min, maintained for 100 min, and the vacuum degree was 0.2 mbar; then warmed to 35°C in 20 min, maintained for 350 min, and the vacuum degree was 0.1 mbar; and the product was obtained.

[0088] The properties of the azithromycin composition for injection obtained in this example are shown in Table 3.

[0089] Comparative Example 3

[0090] The present comparative example provides a preparation process of azithromycin injection composition, comprising the following steps:

[0091] Step 1: The liquid medicine was prepared according to the preparation method in Example 1.

[0092] Step 2: Pre-freezing, the liquid medicine was cooled to -45℃ in 60 min and maintained for 150 min.

[0093] Step 3: Sublimation drying, the pre-frozen sample was warmed to -25℃ in 30 min, maintained for 120 min, and the vacuum degree was 0.2 mbar; then warmed to -5℃ in 30 min, maintained for 1200 min, and the vacuum degree was 0.2 mbar.

[0094] Step 4: Desorption drying, the sublimation-dried sample was warmed to 10℃ in 20 min, maintained for 100 min, and the vacuum degree was 0.2 mbar; then warmed to 35℃ in 20 min, maintained for 350 min, and the vacuum degree was 0.1 mbar; and the azithromycin injection composition was obtained.

[0095] The properties of the azithromycin injection composition obtained in the present comparative example are shown in Table 3.

[0096] Table 3 Comparison of properties of azithromycin injection compositions obtained in Examples 2-4 and Comparative Examples 1-3

[0097]

[0098] As shown in Table 3, the azithromycin injection compositions obtained in Examples 2-4 have more advantages than those in Comparative Examples 1-3 in terms of moisture, reconstitution time, and clarity of the reconstituted solution.

[0099] Example 5

[0100] The stability of the azithromycin injection compositions obtained in Examples 2-4 and Comparative Examples 1 and 3 was investigated. Each azithromycin injection composition was placed at 60℃ for 60 days, and the azithromycin injection compositions placed for different time were taken for investigation. The investigation results are shown in Table 4.

[0101] Table 4 Investigation results of stability

[0102]

[0103]

[0104]

[0105] As shown in Table 4, the injection composition of azithromycin obtained in Examples 2-4 has good stability, and is obviously superior to the injection composition of azithromycin obtained in Comparative Examples 1 and 3.

Claims

1. A process for the preparation of an azithromycin composition for injection, characterized in that, The composition is made of azithromycin: citric acid: sodium hydroxide = 1: (0.86-0.910): (0.34-0.38) by mass ratio, which is prepared according to the following method: Dissolve the prescription amount of 26%-29% citric acid in 40%-60% injection water, dissolve the prescription amount of azithromycin, and obtain a first solution; Dissolve the remaining prescription amount of citric acid in 15%-30% injection water, dissolve the prescription amount of sodium hydroxide, and obtain a second solution; Mix the second solution into the first solution, add injection water to the total amount, stir uniformly, and filter to obtain a liquid medicine, wherein the pH value of the liquid medicine is 6.4-6.8; The liquid medicine is vacuum freeze-dried to obtain an injection azithromycin composition; the vacuum freeze-drying process includes pre-freezing, sublimation drying, and desorption drying in sequence; wherein the pre-freezing is 5°C for 40-60 min, and then cooled to -45--40°C for 120-150 min.

2. The manufacturing process according to claim 1, characterized in that, The sublimation drying is 30 min for temperature rising to -20--30°C, keeping for 120-150 min, and vacuum degree is 0.2 mbar; 30 min for temperature rising to -5-0°C, keeping for 1200 min, and vacuum degree is 0.2 mbar.

3. The production process according to claim 1 or 2, characterized in that, The pre-freezing is 5°C for 60 min, and then cooled to -45°C for 150 min.

4. The production process according to claim 1 or 2, characterized in that, The sublimation drying is 30 min for temperature rising to -20--30°C, keeping for 120 min, and vacuum degree is 0.2 mbar; and then 30 min for temperature rising to -5°C, keeping for 1200 min, and vacuum degree is 0.2 mbar.

5. The manufacturing process of claim 1, wherein, The desorption drying is 20 min for temperature rising to 10°C, keeping for 100 min, and vacuum degree is 0.2 mbar; 20 min for temperature rising to 30-40°C, keeping for 350 min, and vacuum degree is 0.1 mbar.

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