Lincomycin hydrochloride injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a lincomycin hydrochloride injection and a preparation method thereof. The lincomycin hydrochloride injection comprises the following components: lincomycin hydrochloride, thioglycerol, xylitol and water for injection, and the pH value of the injection is 3.0-5.5. Compared with the prior art, the lincomycin hydrochloride injection provided by the invention has good stability, can tolerate high-temperature sterilization, avoids the use of benzyl alcohol, sulfite antioxidants and EDTA-disodium, and improves the safety of clinical medication.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a lincomycin hydrochloride injection and a preparation method thereof. Background Art

[0002] Lincomycin Hydrochloride, chemical name is 6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-6,8-dideoxy-D-erythro-α-D-galactoctinopyranoside hydrochloride monohydrate. It is a lincosamide alkaline antibiotic isolated from Streptomyces, which mainly binds to the 50s subunit of bacterial ribosomes, inhibits peptidyl transferase and inhibits protein synthesis, thereby achieving antibacterial effect.

[0003] Lincomycin hydrochloride injection is a sterile aqueous solution of lincomycin hydrochloride. It is a commonly used antibiotic drug in clinical practice. It is rapidly absorbed after intramuscular injection, widely distributed in the body, has strong penetration of cell tissues, and has a high peak blood concentration. Lincomycin hydrochloride injection produced by the existing prescription process has a high impurity content and functional excipients such as preservatives and antioxidants are present in the prescription. The excipients include benzyl alcohol, disodium EDTA, sodium bisulfite, sodium metabisulfite, sodium acetate, sodium citrate, sodium dihydrogen phosphate, sodium bicarbonate, etc. Among them, benzyl alcohol, disodium EDTA, sodium bisulfite, and sodium metabisulfite are the most commonly used. Benzyl alcohol's metabolism and degradation product, benzaldehyde, is toxic to the central nervous system and is prohibited by the EU for use in children under 2 years old. Sulfite antioxidants are irritating to the skin, eyes, and respiratory tract, can cause allergic reactions, can cause corneal damage, and lead to blindness. Although disodium EDTA can improve the stability of the injection, there is a risk of complexing with calcium ions in the blood to reduce blood calcium concentration.

[0004] Therefore, there is still a need to develop a lincomycin hydrochloride injection with good stability and high safety and a preparation method thereof. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the present invention provides a lincomycin hydrochloride injection and a preparation method thereof, which avoids the use of benzyl alcohol, sulfite antioxidants and EDTA-disodium and improves the safety of the liquid medicine.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] A lincomycin hydrochloride injection contains the following components: lincomycin hydrochloride, thioglycerol, xylitol and water for injection; the pH value of the lincomycin hydrochloride injection is 3.0-5.5.

[0008] Preferably, the lincomycin hydrochloride injection contains 300 g of lincomycin hydrochloride (calculated as lincomycin), 0.4-0.8 g of thioglycerol, and 30-60 g of xylitol per 1000 mL of injection; the pH value of the lincomycin hydrochloride injection is 4.0-5.0, for example, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, etc., and the "about" mentioned here refers to the range generally acceptable to those skilled in the art, for example, ±0.05.

[0009] Preferably, the lincomycin hydrochloride injection contains 300 g of lincomycin hydrochloride (calculated as lincomycin), 0.6 g of thioglycerol, and 45 g of xylitol per 1000 mL of injection; and the pH value of the lincomycin hydrochloride injection is 4.0-5.0.

[0010] Preferably, the lincomycin hydrochloride injection contains 300 g of lincomycin hydrochloride (calculated as lincomycin), 0.4 g of thioglycerol, and 60 g of xylitol per 1000 mL of injection; and the pH value of the lincomycin hydrochloride injection is 4.0-5.0.

[0011] Preferably, the lincomycin hydrochloride injection contains 300 g of lincomycin hydrochloride (calculated as lincomycin), 0.8 g of thioglycerol, and 30 g of xylitol per 1000 mL of injection; and the pH value of the lincomycin hydrochloride injection is 4.0-5.0.

[0012] Another object of the present invention is to provide a method for preparing the above-mentioned lincomycin hydrochloride injection, comprising the following steps:

[0013] Step 1: Weigh 80-90% of the prescribed amount of water for injection, add the prescribed amount of thioglycerol and xylitol, stir and dissolve to obtain solution 1;

[0014] Step 2: Add the prescribed amount of lincomycin hydrochloride to solution 1, stir and dissolve completely to obtain solution 2;

[0015] Step 3: Add the remaining amount of water for injection to solution 2 to make up the volume, filter with a microporous membrane, and fill;

[0016] Step 4: Sterilization and packaging.

[0017] Preferably, the water for injection in step 1 is 90% of the prescribed amount.

[0018] Preferably, the liquid preparation process maintains the liquid preparation temperature at 10-30°C.

[0019] Preferably, the pore size of the microporous filter membrane in step 3 is 0.45 μm or 0.22 μm.

[0020] Preferably, the sterilization in step 4 is carried out at 121° C. for 15 min.

[0021] Compared with the prior art, the present invention has the following beneficial effects: (1) the lincomycin hydrochloride injection of the present invention has good stability and can withstand high-temperature sterilization; (2) thioglycerol is used instead of benzyl alcohol as an antibacterial agent, thereby solving the problem that benzyl alcohol is not friendly to children. DETAILED DESCRIPTION

[0022] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0023] Example 1

[0024] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of thioglycerol, and 45g of xylitol.

[0025] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0026] Example 2

[0027] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.4g of thioglycerol, and 60g of xylitol.

[0028] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0029] Example 3

[0030] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.8g of thioglycerol, and 30g of xylitol.

[0031] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0032] Example 4

[0033] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of thioglycerol, and 45g of xylitol.

[0034] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 10°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0035] Example 5

[0036] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of thioglycerol, and 45g of xylitol.

[0037] Preparation method: Add 80% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 30°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0038] Comparative Example 1

[0039] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 45g of xylitol.

[0040] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0041] Comparative Example 2

[0042] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of thioglycerol.

[0043] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0044] Comparative Example 3

[0045] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of glycerol, and 45g of xylitol.

[0046] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of glycerol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0047] Comparative Example 4

[0048] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of thioglycerol, and 45g of mannitol.

[0049] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of thioglycerol and mannitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0050] Comparative Example 5

[0051] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 9.45g of benzyl alcohol.

[0052] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of benzyl alcohol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0053] Comparative Example 6

[0054] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of benzyl alcohol, and 45g of xylitol.

[0055] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of benzyl alcohol and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0056] Comparative Example 7

[0057] Prescription (calculated based on 1000mL): 300g of lincomycin hydrochloride (calculated as lincomycin), 0.6g of sodium bisulfite, and 45g of xylitol.

[0058] Preparation method: Add 90% of the total water volume of the prescription into the preparation tank, add the prescription amount of sodium bisulfite and xylitol, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and keep the preparation temperature at 20°C during the preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterilizing grade filter element and fill it; finally sterilize at 121°C×15min.

[0059] Product quality testing methods:

[0060] 1. The method for detecting related substances of lincomycin hydrochloride injection described in the present invention is determined by referring to the method for detecting related substances of lincomycin hydrochloride in European Pharmacopoeia EP11.2.

[0061] Mobile phase preparation: methanol: acetonitrile: pH 6.1 buffered saline solution (take 34 g of phosphoric acid, add it to 900 mL of water, adjust the pH to 6.1 with ammonia water, dilute it to 1000 mL with water, mix well, and filter it with a 0.22 μm filter membrane to obtain) = 8:17:75 (v / v / v).

[0062] Test solution: accurately pipette 2 mL of the product into a 50 mL volumetric flask, dilute to the mark with mobile phase, mix well, then accurately pipette 2 mL into a 10 mL volumetric flask, dilute to the mark with mobile phase, mix well, and the solution is ready.

[0063] Reference solution: Weigh an appropriate amount of lincomycin hydrochloride reference substance (equivalent to 22 mg of lincomycin), place it in a 10 mL volumetric flask, add the mobile phase to dissolve it and dilute to the scale.

[0064] Control solution c: Accurately measure 2 mL of the reference solution, place it in a 100 mL volumetric flask, dilute to the mark with the mobile phase, and mix well to obtain a solution containing 44 μg of lincomycin per 1 mL.

[0065] Control solution d: Accurately measure 1 mL of control solution c, place it in a 20 mL volumetric flask, dilute to the mark with the mobile phase, and mix well to obtain a solution containing 2.2 μg of lincomycin per 1 mL.

[0066] Chromatographic conditions: chromatographic column: Welch Ultimate XB-C8 (250mm*4.6mm, 5μm); detector: UV-Detector; column temperature: 50℃; injection volume: 20μL; detection wavelength: 210nm; flow rate: 1.0mL / min; running time: 60min.

[0067] 2. The method for detecting the content of lincomycin hydrochloride injection described in the present invention is as follows: the content of lincomycin hydrochloride is determined according to the method for detecting the content of lincomycin hydrochloride in European Pharmacopoeia EP11.2.

[0068] Mobile phase preparation: methanol: acetonitrile: pH 6.1 buffered saline solution (take 34 g of phosphoric acid, add it to 900 mL of water, adjust the pH to 6.1 with ammonia water, dilute it to 1000 mL with water, mix well, and filter it with a 0.22 μm filter membrane to obtain) = 8:17:75 (v / v / v).

[0069] Test solution: accurately pipette 2 mL of the product into a 50 mL volumetric flask, dilute to the mark with mobile phase, mix well, then accurately pipette 2 mL into a 10 mL volumetric flask, dilute to the mark with mobile phase, mix well, and the solution is ready.

[0070] Reference solution: Weigh an appropriate amount of lincomycin hydrochloride reference substance (equivalent to 22 mg of lincomycin), place it in a 10 mL volumetric flask, add the mobile phase to dissolve it and dilute to the scale. Prepare 2 portions in parallel.

[0071] Chromatographic conditions: chromatographic column: Welch Ultimate XB-C8 (250mm*4.6mm, 5μm); detector: UV-Detector; column temperature: 50℃; injection volume: 20μL; detection wavelength: 210nm; flow rate: 1.0mL / min; running time: 60min.

[0072] 3. The pH detection method of the lincomycin hydrochloride injection described in the present invention: refer to the pH value determination method (General Rule 0631) of the Chinese Pharmacopoeia 2020 edition.

[0073] Lincomycin Hydrochloride Injection Test Item Limits

[0074]

[0075]

[0076] The structures of impurity A, impurity B and impurity C are shown below:

[0077]

[0078] Test 1

[0079] The lincomycin hydrochloride injection samples were tested before and after sterilization to examine the changes in the injection pH value, related substance content and lincomycin content before and after sterilization. The test results are shown in Table 1.

[0080] Table 1

[0081]

[0082]

[0083] According to the results in Table 1, it can be seen that the properties, pH, related substances and contents of the lincomycin hydrochloride injection prepared in Examples 1-5 did not change significantly after high-temperature sterilization, and the stability was good, that is, the lincomycin hydrochloride injection of the present invention tolerated terminal sterilization, while the maximum unknown single impurity and total impurity contents of the lincomycin hydrochloride injection prepared in Comparative Examples 1-7 increased significantly during the high-temperature sterilization process, showing terminal sterilization intolerance.

[0084] Test 2

[0085] The sterilized samples were placed at 40±2°C, 75%RH±5%RH for 1 month. Samples were taken at the beginning (0 day) and end (30 days) of storage, and the samples were measured and compared to analyze the stability of the samples. The results are shown in Table 2.

[0086] Table 2

[0087]

[0088] According to the results in Table 2, it can be seen that the properties, pH, related substances and contents of the lincomycin hydrochloride injection samples prepared in Examples 1-5 did not change significantly after being placed at 40±2°C and 75%RH±5%RH for 30 days, and the stability of the drug solution can be maintained.

[0089] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A lincomycin hydrochloride injection, characterized in that: The invention comprises the following components: lincomycin hydrochloride, thioglycerol, xylitol and water for injection; the pH value of the lincomycin hydrochloride injection is 3.0-5.

5.

2. The injection according to claim 1, characterized in that Each 1000 mL of the injection contains 300 g of lincomycin hydrochloride, 0.4-0.8 g of thioglycerol, and 30-60 g of xylitol, calculated as lincomycin; the pH value of the lincomycin hydrochloride injection is 4.0-5.

0.

3. The injection according to claim 2, characterized in that Each 1000 mL of the injection contains 300 g of lincomycin hydrochloride, 0.6 g of thioglycerol and 45 g of xylitol in terms of lincomycin; the pH value of the lincomycin hydrochloride injection is 4.0-5.

0.

4. The injection according to claim 2, characterized in that: Each 1000 mL of the injection contains 300 g of lincomycin hydrochloride, 0.4 g of thioglycerol and 60 g of xylitol in terms of lincomycin; the pH value of the lincomycin hydrochloride injection is 4.0-5.

0.

5. The injection according to claim 2, characterized in that: Each 1000 mL of the injection contains 300 g of lincomycin hydrochloride, 0.8 g of thioglycerol and 30 g of xylitol, calculated as lincomycin; the pH value of the lincomycin hydrochloride injection is 4.0-5.

0.

6. The method for preparing the lincomycin hydrochloride injection according to any one of claims 1 to 5, characterized in that: The following steps are involved: Step 1: Weigh 80-90% of the prescribed amount of water for injection, add the prescribed amount of thioglycerol and xylitol, and stir to dissolve to obtain solution 1; Step 2: Add the prescribed amount of lincomycin hydrochloride to solution 1, stir and dissolve completely to obtain solution 2; Step 3: Add the remaining amount of water for injection to solution 2 to make up the volume, filter with a microporous membrane, and fill; Step 4: Sterilization and packaging.

7. The preparation method according to claim 6, characterized in that: The water for injection described in step 1 is 90% of the prescribed amount.

8. The preparation method according to claim 6, characterized in that: The liquid preparation temperature is maintained at 10-30°C during the preparation process.

9. The preparation method according to claim 6, characterized in that: The sterilization in step 4 is carried out at 121° C. for 15 min.

Images