Lincomycin hydrochloride injection and a preparation method thereof

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a lincomycin hydrochloride injection and a preparation method thereof. The lincomycin hydrochloride injection contains the following components: lincomycin hydrochloride, thio-glycerol, 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 has good stability, can resist high-temperature sterilization, avoids the use of benzyl alcohol, sulfite antioxidant and EDTA-2Na, and improves the safety of clinical medication.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a lincomycin hydrochloride injection and its preparation method. Background Technology

[0002] Lincomycin hydrochloride, chemically named 6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-6,8-dideoxy-D-erythro-α-D-galactopyranoside hydrochloride monohydrate, is a lincomycin-based basic antibiotic isolated from Streptococcus pneumoniae. It primarily exerts its antibacterial effect by binding to the 50S subunit of bacterial ribosomes, inhibiting peptidyl transferases, and thus suppressing protein synthesis.

[0003] Lincomycin hydrochloride injection is a sterile aqueous solution of lincomycin hydrochloride, a commonly used antibiotic in clinical practice. It is rapidly absorbed after intramuscular injection, widely distributed in the body, has strong penetrating power into cells and tissues, and achieves high peak plasma concentrations. Current formulation processes for producing lincomycin hydrochloride injection result in high impurity content and the presence of preservatives and antioxidants in the formulation. These excipients include benzyl alcohol, disodium EDTA, sodium bisulfite, sodium metabisulfite, sodium acetate, sodium citrate, sodium dihydrogen phosphate, and sodium bicarbonate, with benzyl alcohol, disodium EDTA, sodium bisulfite, and sodium metabisulfite being the most commonly used. Benzaldehyde, a metabolic and degradation product of benzyl alcohol, is toxic to the central nervous system and is prohibited for use in children under 2 years of age in the European Union. Sulfite antioxidants are irritating to the skin, eyes, and respiratory tract, and can cause allergic reactions, corneal damage, and potentially blindness. While disodium EDTA can improve the stability of the injection, it carries the risk of complexing with calcium ions in the blood, leading to a decrease in blood calcium levels.

[0004] Therefore, there is still a need to develop a lincomycin hydrochloride injection solution with good stability and high safety, as well as its preparation method. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention provides a lincomycin hydrochloride injection and its preparation method, which avoids the use of benzyl alcohol, sulfite antioxidants, and EDTA-disodium, thereby improving the safety of the drug solution.

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

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

[0008] Preferably, the lincomycin hydrochloride injection contains 300g of lincomycin hydrochloride (calculated as lincomycin), 0.4-0.8g of thioglycerol, and 30-60g of xylitol per 1000mL 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., where “about” means a range that is generally acceptable to those skilled in the art, such as ±0.05.

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

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

[0011] Preferably, the lincomycin hydrochloride injection contains 300g of lincomycin hydrochloride (calculated as lincomycin), 0.8g of thioglycerol, and 30g of xylitol per 1000mL of injection; 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 to dissolve and obtain solution 1;

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

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

[0016] Step 4: Sterilize and package.

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

[0018] Preferably, the solution preparation process maintains a solution temperature of 10-30℃.

[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 minutes.

[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) Thioglycerin is used instead of benzyl alcohol as a bacteriostatic agent, which solves the problem that benzyl alcohol is not friendly to children. Detailed Implementation

[0022] To better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to specific embodiments. The embodiments are only for the purpose of helping to understand the present invention and should not be regarded as specific limitations of the present invention.

[0023] Example 1

[0024] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.6 g, xylitol 45 g.

[0025] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 20℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0026] Example 2

[0027] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.4 g, xylitol 60 g.

[0028] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 20℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0029] Example 3

[0030] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.8 g, xylitol 30 g.

[0031] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 20℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0032] Example 4

[0033] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.6 g, xylitol 45 g.

[0034] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 10℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the drug solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0035] Example 5

[0036] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.6 g, xylitol 45 g.

[0037] Preparation method: Add 80% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 30℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0038] Comparative Example 1

[0039] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, xylitol 45 g.

[0040] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the mixing temperature at 20℃ 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 sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0041] Comparative Example 2

[0042] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.6 g.

[0043] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, add the prescription amount of thioglycerin, and stir to dissolve; add the prescription amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and maintain the mixing temperature at 20℃ 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 sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0044] Comparative Example 3

[0045] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, glycerin 0.6 g, xylitol 45 g.

[0046] Preparation method: Add 90% of the total prescribed volume of water for injection to the mixing tank, add the prescribed amount of glycerol and xylitol, and stir to dissolve; add the prescribed amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and maintain the mixing temperature at 20℃ during the preparation process; add the remaining prescribed volume of water for injection to make up the volume; filter the drug solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0047] Comparative Example 4

[0048] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, thioglycerin 0.6 g, mannitol 45 g.

[0049] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the solution temperature at 20℃ during the solution preparation process; add the remaining prescription amount of water for injection to make up the volume; filter the solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0050] Comparative Example 5

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

[0052] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the mixing temperature at 20℃ 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 sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0053] Comparative Example 6

[0054] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, benzyl alcohol 0.6 g, xylitol 45 g.

[0055] Preparation method: Add 90% of the total water volume of the prescription to the mixing tank with water for injection, 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 maintain the mixing temperature at 20℃ 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 sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0056] Comparative Example 7

[0057] Prescription (per 1000 mL): Lincomycin hydrochloride (calculated as lincomycin) 300 g, sodium bisulfite 0.6 g, xylitol 45 g.

[0058] Preparation method: Add 90% of the total prescribed volume of water for injection to the mixing tank, add the prescribed amount of sodium bisulfite and xylitol, and stir to dissolve; add the prescribed amount of lincomycin hydrochloride, stir to dissolve completely and mix well, and maintain the mixing temperature at 20℃ during the preparation process; add the remaining prescribed volume of water for injection to make up the volume; filter the drug solution through a 0.22μm sterile filter cartridge and fill it; finally, sterilize at 121℃ for 15min.

[0059] Product quality testing methods:

[0060] 1. The method for detecting related substances in lincomycin hydrochloride injection according to the present invention is as follows: the method for detecting related substances in lincomycin hydrochloride is specified in the European Pharmacopoeia EP11.2.

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

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

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

[0064] Control solution c: Accurately measure 2 mL of the control solution and 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, mix well, and you will get a solution containing 2.2 μg of lincomycin per 1 mL.

[0066] Chromatographic conditions: 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; Run time: 60min.

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

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

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

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

[0071] Chromatographic conditions: 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; Run time: 60min.

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

[0073] Limits for testing Items of Lincomycin Hydrochloride Injection

[0074]

[0075]

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

[0077]

[0078] Experiment 1

[0079] The samples of lincomycin hydrochloride injection were sent for testing before and after sterilization. The changes in pH value, related substance content and lincomycin content of the injection before and after sterilization were examined. The test results are shown in Table 1.

[0080] Table 1

[0081]

[0082]

[0083] According to the results in Table 1, the lincomycin hydrochloride injections prepared in Examples 1-5 did not show significant changes in properties, pH, related substances, and content after high-temperature sterilization, indicating good stability. This means that the lincomycin hydrochloride injections of the present invention are resistant to terminal sterilization. In contrast, the lincomycin hydrochloride injections prepared in Comparative Examples 1-7 showed a significant increase in the maximum unknown single impurity and total impurity content during high-temperature sterilization, indicating inability to tolerate terminal sterilization.

[0084] Experiment 2

[0085] The sterilized samples were placed at 40±2℃ and 75%RH±5%RH for one month. Samples were taken at the beginning (0 days) and the 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, the lincomycin hydrochloride injection samples prepared in Examples 1-5 did not show significant changes in appearance, pH, related substances, and content after being placed at 40±2℃ and 75%RH±5%RH for 30 days, thus maintaining the stability of the drug solution.

[0089] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features. Such modifications or substitutions 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 solution, characterized in that, Each 1000 mL of the injection solution contains 300 g of lincomycin hydrochloride (calculated as lincomycin), 0.4-0.8 g of thioglycerol, and 30-60 g of xylitol; the pH value of the lincomycin hydrochloride injection solution is 4.0-5.

0.

2. The injection solution as described in claim 1, characterized in that, Each 1000 mL of the injection solution contains 300 g of lincomycin hydrochloride, 0.6 g of thioglycerol, and 45 g of xylitol, calculated as lincomycin; the pH value of the lincomycin hydrochloride injection solution is 4.0-5.

0.

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

0.

4. The injection solution as described in claim 1, characterized in that, Each 1000 mL of the injection solution 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 solution is 4.0-5.

0.

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

6. The preparation method according to claim 5, characterized in that, The water for injection mentioned in step 1 is 90% of the prescribed amount.

7. The preparation method according to claim 5, characterized in that, The solution preparation process should be carried out at a temperature of 10-30℃.

8. The preparation method according to claim 5, characterized in that, The sterilization described in step 4 is carried out at 121°C for 15 minutes.

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