A method for preparing an amikacin lotion

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a preparation method of amikacin lotion, which comprises the following steps: weighing raw materials, preparing a sulfuric acid solution, preparing a liquid medicine, adjusting pH and constant volume, filtering and filling, sterilizing and packaging. The pH value of the liquid medicine is accurately controlled at 5.5-6.5, the liquid medicine is sterilized at 115 DEG C for 35 minutes, and the main drug is fully dissolved by heating and dissolving the liquid medicine with hydroxyphenyl ethyl ester and stirring and refluxing the amikacin until the amikacin is completely dissolved in the liquid medicine. The application also provides the content standard 0.232%-0.268% and the microbial limit standard ≤100 CFU / 100 mL of the intermediate product, and the time limit requirements that the liquid medicine is filled within 36 hours after preparation and the liquid medicine is sterilized within 36 hours after filling. The content of the prepared amikacin lotion is not less than 97.0% of the marked amount after being stored at 25 DEG C ± 2 DEG C and RH 60% ± 10% for 24 months. The application has the advantages of simple prescription, controllable process and good stability, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a method for preparing an amikacin lotion. Background Technology

[0002] Amikacin is a semi-synthetic aminoglycoside antibiotic. Its chemical name is o-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-o-[6-amino-6-deoxy-α-D-glucopyranosyl-(1→4)]-N′-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-D-streptomycin, with the molecular formula C2. 22 H 43 N5O 13 With a molecular weight of 585.61, amikacin is stable against most inactivating enzymes, as well as acetyltransferases, phosphotransferases, and nucleoside transferases produced by most intestinal Gram-negative bacilli and Pseudomonas aeruginosa. It is one of the aminoglycoside antibiotics with relatively low resistance among current available antibiotics.

[0003] In existing technologies, the common approach to addressing the stability issue of amikacin aqueous solutions is an additive approach. For example, amikacin sulfate injection improves stability by adding antioxidants such as sodium bisulfite and sodium metabisulfite, as well as buffers such as sodium citrate; amikacin eye drops utilize a boric acid-borax buffer system and add excipients such as sodium chloride; and in the field of amikacin lotion, there have been attempts to formulate compound lotions using amikacin and dexamethasone sodium phosphate. All of these approaches rely on increasing the number of formulation components as their core strategy.

[0004] However, the additive approach has obvious limitations: the increase in the types of excipients leads to increased formulation complexity and introduces potential compatibility risks; compound preparations require the establishment of multi-component content determination methods, which significantly increases the difficulty of quality control; and the production process requires higher standards, which is not conducive to the stable scale-up of industrial production. Summary of the Invention

[0005] To overcome the technical deficiencies of existing technologies, this invention provides a method for preparing amikacin lotion, comprising the following steps:

[0006] Step 1: Weighing and preparing sulfuric acid solution: According to the batch production instructions, weigh the prescribed amounts of amikacin, ethylparaben, and sulfuric acid, with a weighing error of ±1%; slowly add the sulfuric acid to the water for injection while stirring, to prepare a 0.2 mol / L sulfuric acid solution in a plastic bucket.

[0007] Step 2: Prepare the drug solution: Add ethylparaben to water for injection, heat and stir until completely dissolved, then transfer to a mixing tank; then slowly add amikacin to the mixing tank, stir and reflux until the amikacin is completely dissolved; the criteria for complete dissolution are: no amikacin adhering to the tank wall and no suspended amikacin particles in the drug solution;

[0008] Step 3: pH adjustment and volume determination: Add the 0.2 mol / L sulfuric acid solution prepared in Step 1 to the drug solution and adjust the pH value to 5.5-6.5; then add water for injection to the full prescription volume, and continue stirring for 10 minutes before stopping;

[0009] Step 4: Filtration and filling: After filtering the liquid medicine through a 0.22μm sterile filter, fill it into pharmaceutical containers. During the filling process, ensure that the amount in each container is not less than the indicated amount.

[0010] Step 5: Sterilize and package the product: Sterilize the filled and sealed product at 115℃ for 35 minutes. After sterilization, remove unqualified products. After passing the inspection, label and package the product to obtain the finished Amikacin lotion.

[0011] Preferably, in step 2, the amount of ethylparaben added is 30g per 100L of drug solution; the amount of amikacin added is calculated according to the formula: batch production instruction amount = theoretical amount / [content × (1 - loss on drying)] × 100%, and the amount is added at 100% of the prescription amount.

[0012] Preferably, the amount of the 0.2 mol / L sulfuric acid solution prepared in step 1 is as follows:

[0013] a. 100mL / bottle, batch size 5,000 bottles: 453g sulfuric acid, add water to 23.1kg;

[0014] b. 100mL / bottle, batch of 10,000 bottles: 904g of sulfuric acid, add water to 46.1kg;

[0015] c. 100mL / bottle, batch of 20,000 bottles: 1808g of sulfuric acid, add water to 92.2kg;

[0016] d. 50mL / bottle, batch size 20,000 bottles: 904g sulfuric acid, add water to 46.1kg;

[0017] e. 50mL / bottle, batch of 40,000 bottles: 1808g of sulfuric acid, add water to 92.2kg;

[0018] f. 25mL / bottle, batch of 20,000 bottles: 453g of sulfuric acid, add water to 23.1kg.

[0019] Preferably, the intermediate product in step 2 is stored in a sealed container and filled within 36 hours; the product is sterilized within 36 hours after filling.

[0020] Preferably, in step 4, a 12-head filling machine is used for filling. Before filling, the filling volume of each filling head is measured to be no less than the indicated filling volume before production can begin. During the production process, the filling volume is checked every 30 minutes, and adjustments are made in a timely manner if it is not up to standard.

[0021] Preferably, the filter element described in step 4 undergoes a bubble point test before use and an integrity test after production. Only after both tests are passed can the filter element be used and released. The normal use of the filter element shall not exceed 40 batches.

[0022] Preferably, before adjusting the pH in step 3, the pH meter is calibrated according to the standard operating procedure for pH meters; when adjusting the pH, sulfuric acid solution is slowly added, stirred evenly, and then measured.

[0023] Preferably, after sterilization in step 5, the product temperature is allowed to drop below 40°C before inspection, and products with deformed bottles, poor sealing, or leakage are rejected; the sterilization parameters are recorded in the batch production record.

[0024] Preferably, steps 1 to 4 are carried out in a Class C clean area with an operating room temperature of 18℃ to 26℃ and a relative humidity of 15% to 65%. After the volume is adjusted in step 3, the content and microbial limits of the intermediate product are determined. The standards are: amikacin content of 0.232% to 0.268%, and the total number of aerobic bacteria per 100 mL must not exceed 100 CFU. Only after passing the test can the next process be carried out.

[0025] Preferably, the lotion is a colorless or slightly yellow clear liquid with a pH of 5.5–6.5, containing 90.0%–110.0% of the labeled amount of amikacin, and is available in 25mL:62.5mg, 50mL:125mg, or 100mL:250mg formulations. After storage at 25℃±2℃ and RH 60%±10% for 24 months, the lotion content remains no less than 97.0% of the labeled amount. The packaging consists of a polypropylene bottle with a spray pump, encased in a cardboard box. The formulation comprises amikacin, ethylparaben, water for injection, and a pH adjuster, and does not contain antioxidants, buffers, or other active pharmaceutical ingredients.

[0026] The beneficial effects of this invention are:

[0027] 1. The formulation of this invention is simplified, using only ethylparaben as an antibacterial agent and water for injection as a solvent, avoiding the compatibility risks and quality control complexities brought about by compound preparations and multiple excipients; the stability is significantly improved, with the pH precisely controlled within a narrow range of 5.5 to 6.5, combined with terminal sterilization at 115℃ / 35min, the product still maintains a content of over 97% after 6 months of accelerated testing, and a content of no less than 97.7% over a long-term period of 24 months, far exceeding the national standard; the process control is precise, ensuring complete dissolution of amikacin through reflux operation and providing a clear judgment standard, solving the technical problems of incomplete dissolution and uneven content caused by conventional stirring. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the various embodiments of this invention are described in detail below. However, those skilled in the art will understand that many technical details have been provided in the various embodiments of this invention to facilitate a better understanding of this application. However, the technical solutions claimed in the claims of this application can be implemented even without these technical details and with various variations and modifications based on the following embodiments.

[0029] Example 1: Production of 100mL / bottle and batches of 1000 bottles was carried out, and the specific operation was as follows:

[0030] The prescription in this embodiment is as follows: 250g of amikacin, 30g of ethylparaben, and 453g of sulfuric acid to prepare a 0.2mol / L sulfuric acid solution, with water for injection added to a final volume of 100L. The weighing error is controlled within ±1%.

[0031] The preparation method is as follows: In the weighing and preparation of the sulfuric acid solution, the weighing operation is carried out in a Class C cleanroom weighing room with a temperature of 22℃ and a relative humidity of 45%. According to the batch production order, the weighing operator uses a calibrated electronic weighing scale to weigh 250g of amikacin and 30g of ethylparaben, with weighing errors of +0.5% and -0.3%, respectively, both within the range of +1% to -1%. The weighing process is double-checked by another operator, who verifies the material name, batch number, quantity, appearance, etc., and signs to confirm that everything is correct. The weighed materials are placed in clean stainless steel containers, labeled with the product name, specifications, batch number, weight, date, and operator's name, and then transferred to the preparation room in a sealed container. Separately, 453g of sulfuric acid is weighed, with an error of +0.2%, and placed in an acid-resistant plastic container. In the preparation room, 453g of sulfuric acid was slowly added to approximately 20kg of water for injection while stirring. After the addition was complete, stirring continued until homogeneous. Finally, water for injection was added to bring the total volume to 23.1kg, yielding a 0.2mol / L sulfuric acid solution. The preparation container was a plastic bucket. Personnel who underwent specialized training wore latex gloves and protective goggles during the preparation process. Throughout the operation, the sulfuric acid was slowly added to the water to prevent localized overheating and splashing.

[0032] During the drug preparation process, check that the mixing tank is clean, disinfected, and within its expiration date; that the equipment status indicator shows normal operation; and confirm that the operating room temperature is 22℃, relative humidity is 45%, and the pressure difference meets the requirements of a Class C clean area (greater than 10 Pascals). Open the water for injection valve and add approximately 80L of water for injection to the mixing tank, which is about four-fifths of the total 100L of solution to be prepared. Then, turn on the stirring motor. Ethylparaben was placed in a stainless steel container, and approximately 5 L of water for injection was added. The container was heated to approximately 80°C on an induction cooker and stirred. After the ethylparaben was completely dissolved, the resulting ethylparaben solution was poured into a mixing tank, and stirring was continued for approximately 10 minutes. Amikacin was then slowly added to the mixing tank at a rate of approximately 50 g per minute to prevent powder from flying away. After the addition was complete, stirring was continued for approximately 10 minutes. The material pump was then turned on for reflux, with the reflux pipe drawing the solution from the bottom of the tank and allowing it to flow back in from the top, ensuring that the amikacin accumulated on the liquid surface and near the stirrer was completely wetted. After reflux for approximately 5 minutes, the walls of the mixing tank were observed. No visible amikacin adhered to the tank walls. The solution was then observed in a glass sampling bottle. The solution was clear and free of suspended amikacin particles, indicating that the amikacin was completely dissolved. If undissolved amikacin remained, reflux was continued until the above criteria were met. In this example, the total reflux time was approximately 8 minutes to achieve complete dissolution.

[0033] In the pH adjustment and volume adjustment steps, the pH meter was calibrated according to the standard operating procedure for laboratory pH meters. Three standard buffer solutions with pH values ​​of 4.01, 6.86, and 9.18 were used for three-point calibration. After calibration, the slope was greater than 98.0%, confirming that the pH meter was in normal condition. After the amikacin was completely dissolved, about 200 mL of the 0.2 mol / L sulfuric acid solution prepared in step (1) was slowly added using a pipette while stirring. After stirring evenly, a sample was taken to measure the pH value. The pH meter reading was 6.2, which is within the range of 5.5 to 6.5. No further adjustment is required in this embodiment. The material pump was turned off, stirring was stopped, and water for injection was added to 100 L. The drug solution density was controlled by the weighing module. The drug solution density was 1.002 g / mL. The solution was added to 100.20 kg, which is about 100 L. The stirring motor and material pump were turned on, and stirring and reflux were continued for 10 minutes before stopping. According to the standard operating procedure for intermediate product sampling, about 200 mL of intermediate product was taken using a clean sampling bottle and sent to the quality control department for testing. After sampling, the prepared intermediate products are stored in a sealed container.

[0034] During the filtration and filling process, check the installation of the cartridge filter, confirming that the 0.22μm sterilizing filter element is correctly installed in the filter housing. The filter element has passed the bubble point test before use, with a bubble point pressure greater than or equal to 0.35 MPa, and the test is qualified. The feed pipe is properly connected to the discharge port of the mixing tank, and the discharge pipe is properly connected to the storage tank. Open the discharge valve of the mixing tank, close the reflux valve, and start the material pump. The medicine solution is filtered through the 0.22μm pore size cartridge sterilizing filter into the storage tank. During the filtration process, carefully observe the filtration pressure, maintaining it between 0.15 and 0.20 MPa. After filtration, turn off the material pump and collect the residual medicine solution in the pipeline into the storage tank. Transfer the medicine solution in the storage tank to the filling machine's storage tank in filling room 3. Check that the fully automatic servo filling machine has been cleaned and disinfected, and that the trial run is normal, with 12 filling heads. Twelve clean 100mL oral liquid pharmaceutical polypropylene bottles were placed under twelve filling heads for trial filling. The volume of each bottle was weighed using a calibrated electronic balance. The empty bottles were weighed before filling, and the total weight was measured after filling to calculate the net volume. Formal filling production could only proceed if the net volume of each of the twelve filling heads was at least 100mL. During formal filling, the volume of each filling head was measured every 30 minutes using the above method and recorded in the batch production record. If the volume of any filling head was less than 100mL, the machine was immediately stopped, the filling parameters of that filling head were adjusted, and the products filled between the last passing inspection and the current inspection were weighed and sorted, discarding those with unacceptable volume. During the filling process, approximately 12 bottles of 100mL each, totaling about 1.2L, are tested for their volume of the drug solution. These are collected in a clean stainless steel container, labeled with the tested volume of the drug solution, batch number, and date. After weighing and recording, the container is returned to the storage tank before the end of the batch filling. It is then filtered again through a 0.22μm filter before being filled.

[0035] In the sterilization and packaging step, about 1000 bottles of the intermediate product after filling and sealing are subpackaged in a sterilization cart, loaded into a water-bath sterilizer, and the cabinet door is closed. According to the standard operating procedure for the sterilization cabinet, the sterilization temperature is set as 115°C and the sterilization time is set as 35 minutes. Start the sterilization procedure, and the whole process is automatically controlled. During the sterilization process, the sterilization cabinet automatically records the temperature-time curve, and prints the sterilization parameter record after sterilization, including sterilization temperature, time, F0 value, etc., and attach the record to the back of the batch production record. After sterilization is completed, open the cabinet door after the sterilization cabinet displays that door opening is allowed, and take out the sterilization cart. Place the product at room temperature, wait until the product temperature drops below 40°C, use an infrared temperature gun to detect that the bottle body temperature is about 38°C, conduct manual inspection bottle by bottle to observe whether the bottle is deformed, whether the bottle cap is sealed tightly, and whether there is liquid leakage on the bottle body. In this example, 2 deformed products and 1 leaking product are detected, with a total of 3 unqualified products, which are treated as unreusable materials; there are 997 qualified products in total, after counting the quantity, fill in an inspection application form, and the Quality Assurance Department will take samples for inspection. After the sterilized product passes the quality inspection, labeling and packaging are carried out. Using a high-speed labeling machine, first print a label manually, check the label content, including product name, specification, approval number, batch number, production date, expiration date, after confirming that they are consistent with the batch production instruction, use the product for trial labeling, and after the label is flatly attached to the bottle body, conduct continuous labeling. After labeling, load into boxes according to the packaging specification of 1 bottle per box, attach the instruction manual, and pack into outer boxes, 40 boxes per outer box, to obtain the finished product.

[0036] The quality inspection results are shown in the following table:

[0037] .

[0038] In terms of material balance accounting, the filling yield is calculated as: (weight of qualified filled medicinal liquid / total weight of filtered medicinal liquid) × 100%, the result is 98.2%, which is within the standard range of 90.0% to 102.0%, so it is determined as qualified. The filling balance rate is calculated as: (weight of qualified filled medicinal liquid + weight of unreusable medicinal liquid / total weight of filtered medicinal liquid) × 100%, the result is 99.6%, which is within the standard range, so it is determined as qualified. The sterilization balance rate is calculated as: (number of qualified sterilized products + number of unqualified sterilized products / total number before sterilization) × 100%, the result is 100.0%, which is within the standard range of 98.0% to 102.0%, so it is determined as qualified. The finished product rate is calculated as: (quantity of finished products / planned batch size) × 100%, the result is 99.7%, which is within the standard range of 85.0% to 100.0%, so it is determined as qualified.

[0039] Example 2: Production with 50mL per bottle and a batch size of 20000 bottles, the specific operation is as follows: The prescription of this example is: 2.500 kg of amikacin, 300 g of ethylparaben, 904 g of sulfuric acid for preparing 0.2 mol / L sulfuric acid solution, add water for injection to a constant volume of 1000 L. The weighing error range is controlled within ±1%.

[0040] The preparation method refers to Example 1, and the main difference parameters are as follows: in the steps of weighing and batching and preparing sulfuric acid solution, 2.500 kg of amikacin is weighed, with an error of +0.1%, 300 g of ethyl parahydroxybenzoate, with an error of -0.2%, and 904 g of sulfuric acid, with an error of +0.2%. Slowly add 904 g of sulfuric acid into water for injection, stir while adding, add until the total mass reaches 46.1 kg, to obtain 0.2 mol / L sulfuric acid solution.

[0041] In the liquid preparation step, add about 800 L of water for injection into the batching tank, which is about four fifths of the total prepared liquid volume of 1000 L. After ethyl parahydroxybenzoate is dissolved, add it into the batching tank and stir for about 10 minutes. The feeding rate of amikacin is controlled at about 500 g per minute. After the feeding is completed, stir for about 10 minutes, and reflux until completely dissolved, with a reflux time of about 10 minutes.

[0042] In the pH adjustment and constant volume step, after calibrating the pH meter according to the standard operating procedure for pH meters, slowly add about 2.0 L of 0.2 mol / L sulfuric acid solution, stir evenly and measure the pH value as 6.2, which meets the range of 5.5 to 6.5. Add water for injection to a constant volume of 1000 L, controlled by a weighing module, until the mass reaches 1002.00 kg, stop stirring and refluxing after 10 minutes.

[0043] In the filtration and filling step, the medicinal liquid is filtered into the storage tank through a 0.22 μm sterilizing filter. The filling specification is 50 mL per bottle. Before filling, measure the filling volume of 12 filling heads, all of which are above 50 mL, with the actually measured volume being 50.2 to 50.6 mL, before production can be carried out. During the filling process, the filling volume is sampled and inspected every 30 minutes, and all filling volumes are between 50.1 and 50.5 mL, which meets the regulations.

[0044] In the sterilization and packaging step, sterilize at 115°C for 35 minutes. After sterilization, wait until the temperature of the product drops below 40°C, inspect bottle by bottle. 15 deformed bottles and 8 leaking bottles are detected, with a total of 23 unqualified products, and 19977 qualified products. After passing the inspection, label and package, with the specification being 50 mL per bottle per box, and 60 boxes per carton.

[0045] The quality inspection results of the amikacin lotion prepared in this example are shown in the following table:

[0046] .

[0047] 4. Material balance calculation is shown in the following table:

[0048] .

[0049] Example 3: Production with 25 mL per bottle and a batch size of 20,000 bottles, the specific operation is as follows:

[0050] The prescription of this example is: 1.250 kg of amikacin, 150 g of ethyl hydroxybenzoate, and 453 g of sulfuric acid, which is used to prepare a 0.2 mol / L sulfuric acid solution, add water for injection to a final volume of 500 L. The weighing error range is controlled within ±1%.

[0051] The preparation method refers to Example 1, and the main distinguishing parameters are as follows: in the steps of weighing raw materials and preparing the sulfuric acid solution, 1.250 kg of amikacin is weighed with an error of -0.2%, 150 g of ethyl hydroxybenzoate with an error of +0.3%, and 453 g of sulfuric acid with an error of 0%; slowly add 453 g of sulfuric acid into water for injection while stirring, add until the total mass reaches 23.1 kg, to obtain the 0.2 mol / L sulfuric acid solution.

[0052] In the liquid preparation step, add about 400 L of water for injection into the batching tank, which accounts for four-fifths of the total preparation volume of 500 L. After ethyl hydroxybenzoate is dissolved, add it into the batching tank and stir for about 10 minutes; the feeding rate of amikacin is controlled at about 300 g per minute, stir for about 10 minutes after feeding is completed, reflux until it is completely dissolved, and the reflux time is about 9 minutes.

[0053] In the pH adjustment and constant volume step, after calibrating the pH meter according to the standard operating procedure for pH meters, slowly add about 1.2 L of the 0.2 mol / L sulfuric acid solution, stir evenly and measure that the pH value is 5.9, which meets the range of 5.5 to 6.5. Add water for injection to a final volume of 500 L, controlled by a weighing module, add until the total mass reaches 501.00 kg, stop stirring and refluxing after 10 minutes.

[0054] In the filtration and filling step, the medicinal liquid is filtered into the storage tank through a 0.22 μm sterilizing filter; the filling specification is 25 mL per vial. Before filling, measure that the filling volume of 12 filling heads are all above 25 mL, with the actual measured value ranging from 25.1 mL to 25.4 mL, before production can proceed; during the filling process, the filling volume is sampled and inspected every 30 minutes, and all filling volumes are between 25.1 mL and 25.4 mL, which meets the specification.

[0055] In the sterilization and packaging step, sterilize at 115°C for 35 minutes. After sterilization, wait until the temperature of the product drops below 40°C, inspect vial by vial, 12 deformed vials and 6 leaking vials are detected, 18 unqualified products in total, and 19982 qualified products. After passing the inspection, label and package, with the specification of 25 mL per vial per box, and 80 boxes per carton.

[0056] The amikacin lotion prepared in this example is shown in the following table:

[0057] .

[0058] 4. The material balance calculation results are shown in the following table:

[0059] .

[0060] Example 4: Production was carried out with 100 mL per vial and a batch size of 20,000 vials, and the specific operations are as follows:

[0061] The prescription of this example is: 5.000 kg of amikacin, 600 g of ethylparaben, 1808 g of sulfuric acid, which is used to prepare 0.2 mol / L sulfuric acid solution, and water for injection is added to a total volume of 2000 L. The weighing error range is controlled within ±1%.

[0062] The preparation method refers to Example 1, and the main difference is that the batch size is scaled up to 2000 L: in the steps of weighing and material preparation and sulfuric acid solution preparation, 5.000 kg of amikacin is weighed, with an error of +0.1%, 600 g of ethylparaben, with an error of -0.2%, and 1808 g of sulfuric acid, with an error of 0%. Slowly add 1808 g of sulfuric acid into about 80 kg of water for injection while stirring, add until the total mass reaches 92.2 kg, to obtain 0.2 mol / L sulfuric acid solution.

[0063] In the liquid medicine preparation step, add about 1600 L of water for injection into the batching tank, which is four fifths of the total liquid preparation volume of 2000 L. After ethylparaben is dissolved, add it into the batching tank and stir for about 10 minutes. The feeding rate of amikacin is controlled at about 1000 g per minute, after the feeding is completed, stir for about 10 minutes, reflux until it is completely dissolved, and the reflux time is about 15 minutes.

[0064] In the pH adjustment and constant volume step, after calibrating the pH meter according to the standard operating procedure for pH meters, slowly add about 4.2 L of 0.2 mol / L sulfuric acid solution, stir evenly and measure the pH value as 6.0, which meets the range of 5.5 to 6.5. Add water for injection to a constant volume of 2000 L, stop stirring and refluxing after 10 minutes.

[0065] In the filtration and filling step, the liquid medicine is filtered through a 0.22 μm sterilizing filter into a storage tank. The filling specification is 100 mL per vial, and the filling volume is measured to be not less than 100 mL before filling. During the filling process, the filling volume is sampled and inspected every 30 minutes, and all meet the specification.

[0066] In the sterilization and packaging step, sterilize at 115°C for 35 minutes. After sterilization, wait until the temperature of the product drops below 40°C, inspect each vial one by one, 8 deformed vials and 5 leakage vials are detected, totaling 13 unqualified products, and 19987 qualified products. Label and package after passing the inspection.

[0067] The quality inspection results obtained in this example are shown in the following table:

[0068] .

[0069] Example 5: Precision verification of the intermediate product content determination method is carried out, and the specific operations are as follows:

[0070] The intermediate product obtained after the pH adjustment and volume adjustment steps in Example 1 was used to determine the amikacin content by high performance liquid chromatography to examine the precision of the method.

[0071] The chromatographic conditions were as follows: the column was an octadecylsilane-bonded silica column with dimensions of 4.6 mm x 250 mm and a packing particle size of 5 μm; the mobile phase was a mixture of phosphate buffer (pH 3.0) and acetonitrile at a ratio of 95:5; the detection wavelength was 225 nm; the flow rate was 1.0 mL per minute; and the injection volume was 20 μL.

[0072] In the precision test, the same batch of intermediate product (i.e., the intermediate product of Example 1) was injected six times consecutively, and the peak area of ​​amikacin was measured to calculate the relative standard deviation of the content. The content results of the six measurements were 99.2%, 99.4%, 99.1%, 99.3%, 99.2%, and 99.5% of the labeled amount, with an average of 99.3% and a relative standard deviation of 0.15%. The results indicate that the method has good precision, with a relative standard deviation of less than 2.0%, and can be used for the content detection of intermediate products.

[0073] Example 6: Verification of Amikacin Dosage. The specific operation is as follows: Calculate the amount of amikacin to be added according to the dosage formula and verify its accuracy. The content of the amikacin raw material, calculated as anhydrous, is 98.5%, and the loss on drying is 3.0%. The theoretical dosage is 250g per 100L of solution. The dosage is calculated according to the following formula: Batch production order quantity equals theoretical dosage divided by raw material content multiplied by (- minus loss on drying) multiplied by 100%. Specifically, 250g divided by 98.5% multiplied by (- minus 3.0%) multiplied by 100%, which is 250g divided by 98.5% multiplied by 97.0% multiplied by 100%, equals 250g divided by 95.545% multiplied by 100%, resulting in 261.66g. Amikacin raw material was weighed according to the calculated feed amount of 261.66g and produced according to the preparation method of Example 1. The content of the obtained product was determined to be 99.3% of the labeled amount, which meets the requirement of 90.0% to 110.0%. This indicates that the feed amount calculation formula is accurate and reliable and can be used as a standard calculation formula in production.

[0074] Comparative Example 1: The formulation of this comparative example is the same as that of Example 1, i.e., 100 mL / bottle, with a batch size of 1000 bottles.

[0075] The preparation method is the same as in Example 1, except that the control range in the pH adjustment step is different. This comparative example uses a wider pH range specified by the national drug standard, namely 5.0 to 7.0. In the specific operation, the pH value is controlled at 5.5, which is near the lower limit, in order to examine the effect of the wide pH range on the stability of the product.

[0076] The initial quality inspection results are shown in the table below:

[0077] .

[0078] The comparative example and Example 1 were subjected to accelerated stability testing, and were placed under accelerated conditions of 40℃±2℃ and 75%±5% relative humidity for 6 months. The results of the comparative test are shown in the table below:

[0079] .

[0080] After 6 months of accelerated testing, the content of the comparative example decreased to 90.3%, close to the lower limit of the national standard of 90.0%, and the total impurities increased from 0.30% to 1.8%, far exceeding the standard limit of less than or equal to 1.0%. In contrast, the content of Example 1 remained at 97.3%, and the total impurities increased only from 0.28% to 0.52%, which was far superior to the comparative example.

[0081] This comparative example demonstrates that even with identical process conditions, controlling the pH value only within a relatively wide range (5.0 to 7.0, specifically the lower limit of 5.5) results in significantly lower long-term product stability compared to the product of this invention, which precisely controls the pH value within a narrow range of 5.5 to 6.5. This indicates that precise pH control is a key technical feature of this invention for ensuring product stability.

[0082] Comparative Example 2: The formulation of this comparative example is the same as that of Example 1, i.e., 100mL / bottle, with a batch size of 1000 bottles. The specific operation is as follows:

[0083] The preparation method is the same as in Example 1, except that in the drug solution preparation step, after adding amikacin, only conventional stirring is performed for about 20 minutes, and the material pump is not turned on for reflux operation.

[0084] After stirring for about 20 minutes, a small amount of amikacin was still visible on the tank wall and near the stirrer, and extremely fine suspended particles were visible in the liquid. After stirring for another 30 minutes, the amount of residue on the tank wall decreased but did not completely disappear, and suspended particles were still visible. Finally, stirring was extended to 60 minutes, but the criteria for complete dissolution of amikacin, namely no residue on the tank wall and no suspension in the liquid, could not be met.

[0085] Content was determined by sampling at different locations. The content of the sample near the liquid surface at the top of the tank was 95.2% of the labeled amount, the content of the sample in the middle of the tank was 99.1% of the labeled amount, and the content of the sample near the discharge port at the bottom of the tank was 100.3% of the labeled amount. The content varied significantly at different locations, with a relative standard deviation of 2.6%, indicating that incompletely dissolved amikacin caused uneven drug content in the solution.

[0086] This comparative example demonstrates that amikacin has certain solubility characteristics in aqueous solutions. Amikacin accumulated on the liquid surface and near the stirrer is not easily wetted and dissolved by conventional stirring. Without reflux, even with extended stirring time, complete dissolution is difficult to achieve, resulting in uneven drug content and severely affecting product quality. The reflux operation of this invention is a necessary technical means to ensure complete dissolution of amikacin and uniform drug content.

[0087] Comparative Example 3: The formulation of this comparative example is the same as that of Example 1, i.e., 100mL / bottle, batch size 1000 bottles; specific operation instructions are as follows:

[0088] The preparation method is the same as in Example 1, except that the sterilization conditions are different. This comparative example uses sterilization at 121°C for 15 minutes, which is the terminal sterilization condition commonly used for injections; Example 1 uses sterilization at 115°C for 35 minutes.

[0089] The initial quality inspection results are shown in the table below:

[0090] .

[0091] Sterilization at 121℃ for 15 minutes reduced the initial purity of the product to 97.6%, a decrease of approximately 1.6% compared to before sterilization, while the total impurities increased to 0.65%, close to the standard limit of ≤1.0%. In contrast, sterilization at 115℃ for 35 minutes maintained the initial purity at 99.4%, with total impurities at only 0.28%. Although both sterilization conditions achieved sterility assurance with F0 values ​​greater than or equal to 8, the higher heat intensity of 121℃ for 15 minutes resulted in a more significant destructive effect on the active pharmaceutical ingredient, amikacin.

[0092] This comparative example demonstrates that selecting suitable sterilization conditions is crucial for ensuring product content and purity. The sterilization condition of 115°C for 35 minutes used in this invention ensures a high level of sterility while maximally protecting the active pharmaceutical ingredient, amikacin, from heat damage.

[0093] Comparative Example 4: The formulation of the comparative example is the same as that of Example 2, i.e., 50mL / bottle, batch size 20,000 bottles; the specific operation is as follows: the preparation method is the same as that of Example 2, except that the intermediate product prepared in the drug solution preparation step is placed at room temperature in the preparation room for 72 hours before filling, and the filled product is placed for 72 hours before sterilization.

[0094] The results of the microbial limit tests are shown in the table below:

[0095] .

[0096] After 72 hours of storage, the microbial limit increased from less than 10 CFU per 100 mL to 80 CFU. Although sterilization was performed, aerobic bacteria were still detected in the 72-hour sterilization group, indicating that sterilization at 115°C for 35 minutes is insufficient to ensure complete sterilization when the microbial load is too high.

[0097] This comparative example demonstrates that the time limit control requirements of completing filling within 36 hours after preparation and sterilization within 36 hours after filling are of great significance for ensuring the microbiological quality and aseptic assurance level of the product, and are a key component of the whole-process quality control system of this invention.

[0098] Summary of stability tests: For accelerated stability testing, samples prepared in Examples 1 to 4 and Comparative Example 1 were placed under accelerated conditions (40℃ ± 2℃, relative humidity 75% ± 5%) for 6 months, with periodic sampling to detect the content. The test results are shown in the table below:

[0099] .

[0100] Accelerated testing results showed that the content of each embodiment of the present invention remained between 96.9% and 97.4% after 6 months, with a small decrease in content, approximately 1.8% to 2.3%. In contrast, the content of Comparative Example 1 decreased to 90.3%, close to the non-compliance threshold of 90.0% (the lower limit of the national standard), and the decrease reached 8.8%. The stability of the present invention under accelerated conditions is significantly better than that of the comparative example. Long-term stability testing involved placing the sample obtained in Example 1 under long-term conditions (25℃ ± 2℃, relative humidity 60% ± 10%) for 24 months, with periodic sampling to detect content, pH value, related substances, and properties.

[0101] The experimental results are shown in the table below:

[0102] .

[0103] Long-term stability tests showed that the amikacin lotion prepared according to this invention maintained a content of 97.7% after 24 months of long-term storage, with minimal pH changes between 5.7 and 6.0, and a slow increase in total impurities from 0.28% to 0.55%, well below the 1.0% limit, while exhibiting no change in properties. Based on the content degradation rate, the product can maintain a content of over 95% after 36 months of storage at room temperature, indicating that the actual shelf life of the product exceeds 24 months.

[0104] Process parameter study: To further verify the effect of pH on the stability of amikacin lotion, based on Example 1, the pH of the solution was adjusted to 5.0, 5.5, 6.0, 6.5, and 7.0, respectively, while other conditions remained the same. The solution was then placed under accelerated conditions (40℃±2℃) for 6 months, and the content was determined. The experimental results are shown in the table below:

[0105] .

[0106] The results showed that amikacin exhibited the best stability at a pH around 6.0, with the smallest content decrease of -2.1%. The content decrease was -4.6% at pH 5.5 and -5.6% at pH 7.0, both significantly greater than the decrease at pH 6.0. When the pH dropped to 5.0, the content decrease reached as high as -7.2%. Therefore, precisely controlling the pH within the range of 5.5 to 6.5, especially around 6.0, can maximize the stability of amikacin during storage. The stability at pH 6.5 was similar to that at pH 6.0, further supporting the scientific validity and rationality of the selected pH range of 5.5 to 6.5 in this invention. This range avoids the increase of impurities under acidic conditions while ensuring the uniformity of product content throughout its shelf life.

[0107] Those skilled in the art will understand that the above embodiments are specific examples of implementing the present invention, and in practical applications, various changes in form and detail may be made without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing an amikacin lotion, characterized in that: Includes the following steps: Step 1: Weighing and preparing sulfuric acid solution: According to the batch production instructions, weigh the prescribed amounts of amikacin, ethylparaben, and sulfuric acid, with a weighing error of ±1%; slowly add the sulfuric acid to the water for injection while stirring, to prepare a 0.2 mol / L sulfuric acid solution. Step 2: Prepare the drug solution: Add ethylparaben to water for injection, heat and stir until completely dissolved, then transfer to a mixing tank; then slowly add amikacin to the mixing tank, stir and reflux until the amikacin is completely dissolved; Step 3: pH adjustment and volume determination: Add the 0.2 mol / L sulfuric acid solution prepared in Step 1 to the drug solution and adjust the pH value to 5.5-6.5; then add water for injection to the full prescription volume, and continue stirring for 10 minutes before stopping; Step 4: Filtration and filling: After filtering the liquid medicine through a 0.22μm sterile filter, fill it into pharmaceutical containers. During the filling process, ensure that the amount in each container is not less than the indicated amount. Step 5: Sterilize and package the product: Sterilize the filled and sealed product at 115℃ for 35 minutes. After sterilization, remove unqualified products. After passing the inspection, label and package the product to obtain the finished Amikacin lotion.

2. The method for preparing amikacin lotion according to claim 1, characterized in that, In step 2, the amount of ethylparaben added is 30g per 100L of drug solution; the amount of amikacin added is calculated according to the formula: batch production instruction amount = theoretical amount / [content × (1 - loss on drying)] × 100%, and the amount is added at 100% of the prescription amount.

3. The method for preparing amikacin lotion according to claim 1, characterized in that, The amount of 0.2 mol / L sulfuric acid solution prepared in step 1 is as follows: a. 100mL / bottle, batch size 5,000 bottles: 453g sulfuric acid, add water to 23.1kg; b. 100mL / bottle, batch of 10,000 bottles: 904g of sulfuric acid, add water to 46.1kg; c. 100mL / bottle, batch of 20,000 bottles: 1808g of sulfuric acid, add water to 92.2kg; d. 50mL / bottle, batch size 20,000 bottles: 904g sulfuric acid, add water to 46.1kg; e. 50mL / bottle, batch of 40,000 bottles: 1808g of sulfuric acid, add water to 92.2kg; f. 25mL / bottle, batch of 20,000 bottles: 453g of sulfuric acid, add water to 23.1kg.

4. The method for preparing amikacin lotion according to claim 1, characterized in that, The intermediate product in step 2 is stored in a sealed container and filled within 36 hours; the filled product is sterilized within 36 hours.

5. The method for preparing amikacin lotion according to claim 1, characterized in that, In step 4, a 12-head filling machine is used for filling. Before filling, the filling volume of each filling head is measured to be no less than the indicated filling volume before production can begin. During the production process, the filling volume is checked every 30 minutes, and adjustments are made in a timely manner if it is not up to standard.

6. The method for preparing amikacin lotion according to claim 1, characterized in that, In step 4, the filter element undergoes a bubble point test before use and an integrity test after production. Only after both tests are passed can the filter element be used and released. The normal use of the filter element should not exceed 40 batches.

7. The method for preparing amikacin lotion according to claim 1, characterized in that, Before adjusting the pH in step 3, calibrate the pH meter according to the standard operating procedure for pH meters; when adjusting the pH, slowly add sulfuric acid solution, stir evenly, and then measure.

8. The method for preparing amikacin lotion according to claim 1, characterized in that, After sterilization in step 5, wait for the product temperature to drop below 40℃ before inspecting it. Discard any products with deformed bottles, loose seals, or leaks. Record the sterilization parameters in the batch production record.

9. The method for preparing amikacin lotion according to claim 1, characterized in that, Steps 1 to 4 are carried out in a Class C clean area with an operating room temperature of 18℃ to 26℃ and a relative humidity of 15% to 65%. After the volume is adjusted in step 3, the content and microbial limits of the intermediate product are determined. The standards are: amikacin content of 0.232% to 0.268%, and the total number of aerobic bacteria per 100 mL must not exceed 100 CFU. Only after passing the test can the next process be carried out.

10. A method for preparing amikacin lotion according to any one of claims 1 to 9, characterized in that, The lotion is a colorless or slightly yellow clear liquid with a pH of 5.5–6.

5. The amikacin content is 90.0%–110.0% of the labeled amount, and it is available in 25mL:62.5mg, 50mL:125mg, or 100mL:250mg formulations. After storage at 25℃±2℃ and RH 60%±10% for 24 months, the content of the lotion is not less than 97.0% of the labeled amount. It is packaged in a polypropylene bottle with a spray pump, and an outer cardboard box. The formulation consists of amikacin, ethylparaben, water for injection, and a pH adjuster, and does not contain antioxidants, buffers, or other active pharmaceutical ingredients.