Omeprazole sodium lyophilized powder for injection and preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a lyophilized powder injection of omeprazole sodium and a preparation method thereof. The lyophilized powder injection of omeprazole sodium obtained by the pharmaceutical prescription and the preparation process has the advantages of significantly reduced impurity content, significantly improved stability, greatly shortened lyophilization time, and significantly enhanced safety, and can be directly used in clinical treatment.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to an omeprazole sodium lyophilized powder injection and its preparation method. Background Technology

[0002] Omeprazole, a proton pump inhibitor, selectively inhibits H+-K+-ATPase (the proton pump) in gastric parietal cells, thus exerting a strong inhibitory effect on gastric acid secretion induced by various stimuli (histamine, food, acetylcholine, and pentagastrin, etc.). Its chemical name is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, and its molecular structure is as follows:

[0003]

[0004] Omeprazole was first synthesized by AstraZeneca (now AstraZeneca) in Sweden in 1979. Its efficacy was confirmed in 1983, and it was marketed in 1987. In 1989, omeprazole was approved by the U.S. Food and Drug Administration (FDA), becoming the first drug approved for marketing in the United States. Omeprazole is one of the most widely used prescription drugs internationally, and it is also used as an over-the-counter drug in some countries. Its indications include: bleeding from peptic ulcers and anastomotic ulcers; acute gastric mucosal damage caused by stress and acute gastric mucosal injury caused by nonsteroidal anti-inflammatory drugs (NSAIDs); prevention of upper gastrointestinal bleeding caused by severe illness (such as cerebral hemorrhage, severe trauma, etc.) and after gastric surgery; and as an alternative therapy when oral therapy is not applicable for the following conditions: duodenal ulcers, gastric ulcers, reflux esophagitis, and Zollinger-Ellison syndrome.

[0005] Omeprazole is unstable to light, heat, metal ions and oxygen. Currently, the marketed intravenous drip dosage form is a lyophilized powder injection. However, the existing dosage form uses activated carbon adsorption or adds antioxidants to prevent oxidation during the preparation process, which increases the preparation process or the types of excipients, increases the impurity content and has poor stability.

[0006] Chinese patents CN104666255A and CN103169674A disclose a method for preparing lyophilized omeprazole sodium for injection. The preparation process uses activated carbon adsorption, which increases the preparation steps and introduces insoluble impurities, resulting in increased impurity content and poor stability and safety. Furthermore, the method uses a large amount of water for injection and has a long freeze-drying time, which greatly increases the production cost.

[0007] Chinese patent CN102151264A discloses a method for preparing an injectable omeprazole sodium composition. By treating the rubber stopper to remove the exudate, the visible foreign matter and insoluble particles in the product are reduced. However, this method still leads to an increase in impurity content and poor stability and safety.

[0008] It is evident that existing methods for preparing injectable omeprazole sodium involve complex procedures and exhibit poor stability over long periods, hindering clinical application. Therefore, to reduce the impurity content in lyophilized injectable omeprazole sodium powder, enhance stability, and simplify the preparation process, there is an urgent need for a lyophilized injectable omeprazole sodium powder and its preparation method that offers significant advantages such as significantly reduced impurity content, significantly improved stability, greatly shortened lyophilization time, and significantly enhanced safety, allowing for direct clinical use. Summary of the Invention

[0009] To address the existing deficiencies and shortcomings, this application provides an injectable omeprazole sodium lyophilized powder injection and its preparation method. The injectable omeprazole sodium lyophilized powder injection obtained by the specific drug formulation and preparation process of this invention has significantly reduced impurity content, significantly improved stability, greatly shortened lyophilization time, and significantly enhanced safety, and can be directly used in clinical practice.

[0010] This invention is achieved through the following means:

[0011] A lyophilized omeprazole sodium injection for injection comprises omeprazole sodium, disodium ethylenediaminetetraacetate (EDTA), and sodium hydroxide; water is also added during the preparation of the lyophilized powder injection; the preparation process of the lyophilized powder injection requires secondary stoppering and nitrogen filling to control the residual oxygen content to ≤0.65%.

[0012] In some implementations, the water is water for injection.

[0013] In some embodiments, the omeprazole sodium is in the form of 40 to 90 parts by weight.

[0014] In some embodiments, the amount of water for injection added to every 40 to 90 parts by weight of the omeprazole sodium is 1.5 to 2.0 parts by volume; wherein the correspondence between parts by weight and parts by volume is mg:mL.

[0015] In some embodiments, the omeprazole sodium is in the form of 40, 60, or 90 parts by weight. In some preferred embodiments, the omeprazole sodium is in the form of 60 parts by weight.

[0016] In some preferred embodiments, the water for injection is 1.5 parts by volume.

[0017] In some embodiments, the amount of EDTA is ≥2.25 parts by weight; preferably, the amount of EDTA is 2.25 parts by weight.

[0018] This invention also provides a method for preparing lyophilized omeprazole sodium for injection, which is prepared according to the following steps:

[0019] (1) Preparation of drug solution: Dissolve omeprazole sodium and EDTA in water for injection; the amount of water for injection is 75-80% of the total volume fraction;

[0020] (2) Adjust pH: Adjust the pH value of the solution, then add water for injection, and filter to obtain the filtrate;

[0021] (3) Sample freeze-drying: The filtrate is filled, pre-frozen, freeze-dried, and desorption-dryed, and then stoppered to obtain freeze-dried samples;

[0022] (4) After the freeze-dried sample is filled with nitrogen to a pressure of -120mbar to -80mbar, it is first plugged; then the second plugging is performed to control the residual oxygen content to ≤0.65%, and the freeze-dried powder injection is obtained after being removed from the box and capped.

[0023] In some implementations, the pH is adjusted to 10.5 to 11.1 in step (2); preferably, the pH is adjusted to 10.8.

[0024] In step (1), the dissolution temperature is 18-26℃; preferably, the dissolution temperature is 22℃; the dissolution time is <8h; preferably, the dissolution time is <30min.

[0025] In some preferred embodiments, in step (3):

[0026] The pre-freezing treatment is as follows: pre-freeze at -44 to -46°C for 0.8 to 1.2 hours while maintaining a vacuum state;

[0027] The freeze-drying process is as follows: freeze-drying at a temperature of -25℃ to 10℃ while maintaining a vacuum of 0.16 to 0.20 mbar for 12 to 13 hours;

[0028] The desorption drying process is as follows: at a temperature of 20℃~40℃, a vacuum of 0.08~0.12mbar is maintained for desorption drying for 4.5~5.5h.

[0029] In some implementations, the number of filtrations in step (2) is 2 to 5, preferably 3; the filtration pressure is ≤5 bar, preferably ≤3 bar;

[0030] The filtration process uses polyethersulfone (PES) filter cartridges with a pore size of 0.22–0.45 μm. During filtration, the pore size of the PES filter cartridge used later does not exceed that of the PES filter cartridge used earlier.

[0031] In some preferred embodiments, step (2) involves three filtrations at a pressure ≤ 3 bar.

[0032] First filtration: Under filtration pressure <3 bar, a 0.45 μm polyethersulfone filter cartridge is used to filter and obtain the filtrate;

[0033] Second filtration: Under filtration pressure <3 bar, a 0.22 μm polyethersulfone filter cartridge is used to filter the filtrate that has completed the first filtration to obtain the filtrate.

[0034] Third filtration: Under filtration pressure <3 bar, a 0.22 μm polyethersulfone filter cartridge is used to filter the filtrate that has completed the second filtration to obtain the filtrate.

[0035] In some preferred embodiments, the lyophilized powder injection is administered via intravenous drip during drug treatment.

[0036] The beneficial effects of this application are as follows:

[0037] This application provides a lyophilized omeprazole sodium for injection and its preparation method. The formulation and preparation process are optimized. Compared with formulations and / or preparation processes obtained by other methods, the lyophilized omeprazole sodium for injection obtained by this invention has significantly reduced impurity content, significantly improved stability, greatly shortened lyophilization time, and significantly enhanced safety, making it directly applicable to clinical use. Specifically:

[0038] 1) By changing the number of stoppering cycles and the amount of residual oxygen, the impurity content of the lyophilized powder injection was significantly reduced, the stability of the formulation was significantly enhanced, and the shelf life was extended;

[0039] Compared to the stoppering process with only one stoppering and controlling residual oxygen ≤0.65% and the stoppering process with two stoppers without controlling residual oxygen ≤0.65%, the formulation obtained by using two stoppers and controlling residual oxygen ≤0.65% has the lowest impurity content, the best stability, and significantly extends the product's shelf life.

[0040] 2) Changing the dosage of water for injection significantly shortens the lyophilization time and improves the lyophilization efficiency;

[0041] Compared to other ranges of water for injection dosage, when 1.5 to 2.0 parts by volume of water for injection are added to 60 to 90 parts by weight of omeprazole sodium, the formulation exhibits good properties and good solubility. When the dosage of omeprazole sodium is 60 parts by weight and the dosage of water for injection is 1.5 parts by volume, the formulation exhibits the best properties and solubility, the shortest lyophilization time, and the lowest energy consumption.

[0042] 3) Changing the pH of the intermediate drug solution significantly reduces the generation of impurities and improves the stability of the formulation;

[0043] Compared with the pH range of intermediate drug solutions, when the pH is controlled at 10.5 to 11.1, the impurity content is significantly reduced and the stability is good; when the pH is 10.8, the lyophilized powder injection has the lowest impurity content and the best stability.

[0044] 4) Changing the amount of EDTA significantly improved the stability and safety of the formulation;

[0045] Compared to other ranges of EDTA dosage, when the dosage is controlled at ≥2.25 parts by weight, the content of impurities in the formulation is significantly reduced and the stability is good; when the dosage of EDTA is 2.25 parts by weight, the impurity content is the lowest and the stability is the best; at the same time, it can significantly reduce the incidence of hypocalcemia caused by long-term use of the drug and enhance safety.

[0046] 5) No activated charcoal added: Significantly improves formulation stability;

[0047] Compared with the formulations obtained by adding activated carbon in the prior art, the preparation process of this application without adding activated carbon is simple and avoids the introduction of other impurities and the contamination of clean areas and air conditioning systems.

[0048] 6) No antioxidants added: significantly improves formulation safety;

[0049] Compared to formulations obtained by adding antioxidants in existing technologies, the preparation process of this application without adding antioxidants is simple, significantly reduces the risk of clinical use, and significantly improves safety.

[0050] The formulation of the present invention is a lyophilized powder injection of omeprazole sodium for injection with significantly reduced impurity content, significantly improved stability, greatly shortened freeze-drying time, and significantly enhanced safety. Attached Figure Description

[0051] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0052] Figure 1 For the comparison of the effect of water for injection dosage on the properties of the finished product in Example 3 of the present invention, the water for injection dosages from left to right are 1.5 mg, 1.8 mg, 2.0 mg, 1.0 mg, and 1.2 mg, respectively;

[0053] Figure 2 The image shows a comparison of the EDTA dosage and the solution properties of the preparation within 15 hours in Example 5 of this invention. From left to right, the images show the blank control solution and the solutions with EDTA dosages of 2.25 mg, 1.8 mg, 2.0 mg, and 5.0 mg. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] Example 1:

[0056] 1-1. Preparation process:

[0057] The product prescription is shown in the table below:

[0058] Table 1 Product Prescription

[0059] Element content Omeprazole sodium 60mg EDTA 2.25mg Sodium hydroxide 0.98mg Water for Injection 1.5mL

[0060] (1) Preparation of drug solution: According to the product prescription shown in the table above, add EDTA to 80% of the prescription amount of water for injection (water temperature controlled at 22℃), stir to dissolve, then add omeprazole sodium and stir to dissolve;

[0061] (2) pH adjustment: The pH of the solution obtained in step (1) was adjusted to 10.8 using 2 mol / L sodium hydroxide. Then, water for injection was added to obtain the final product concentration. The following filtration process was then performed:

[0062] First filtration: Under filtration pressure <3 bar, filter once using a 0.45 μm polyethersulfone filter cartridge, and take samples to test for microbial limits;

[0063] Second filtration: Under filtration pressure <3 bar, filter once using a 0.22 μm polyethersulfone filter cartridge. After sampling this intermediate and testing its properties, pH value, content, and bacterial endotoxin levels, and confirming that all are within acceptable limits, perform a third filtration.

[0064] Third filtration: Sterilization filtration using a 0.22μm polyethersulfone filter cartridge under filtration pressure <3 bar.

[0065] Table 2 Intermediate Quality Standards

[0066] Test items Limit Standards Properties Colorless clear liquid pH value 10.5～11.1 Omeprazole sodium content 90％～110％ Bacterial endotoxins Less than 6.0 EU

[0067] (3) Sample freeze-drying: The filtrate obtained in step (2) is filled into vials, with a volume of 1.5 mL / vial;

[0068] After freeze-drying and analytical drying, the sample was partially stoppered (i.e., the stopper was placed until it was halfway submerged in the bottle opening) to obtain the freeze-dried sample.

[0069] The pre-freezing conditions are as follows: pre-freeze at -45℃ for 1 hour, then remove the vacuum.

[0070] The freeze-drying conditions were: sublimation drying for 13.5 h at a temperature of -25℃ to 10℃ and a vacuum of 0.18 mbar;

[0071] The desorption and drying conditions were as follows: desorption and drying for 5 hours at a temperature of 20℃~40℃ and a vacuum degree of 0.10mbar.

[0072] (4) Fill the vial with nitrogen to make the pressure inside the vial -120mbar to -80mbar and perform the first stoppering process; then perform the second stoppering process to make the residual oxygen content inside the vial ≤0.65% and obtain the lyophilized powder injection after being removed from the box and capped.

[0073] Table 3. Control conditions for the preparation process

[0074]

[0075]

[0076] Example 2: Selection of plugging and residual oxygen

[0077] Referring to the formulation and preparation process of Example 1, the stoppage and residual oxygen content during the preparation process were changed:

[0078] Example 1: Two compression tests were performed (to control residual oxygen ≤ 0.65%).

[0079] Method 1: Use a single plugging operation (control residual oxygen ≤ 0.65%);

[0080] Method 2: Use two plugging operations (without controlling residual oxygen ≤0.65%);

[0081] The formulations and preparation process controls for other products are the same as in Example 1.

[0082] The quality standards for intermediates are the same as in Example 1.

[0083] Example 3: Selection of the dosage of water for injection

[0084] Referring to the formulation and preparation process of Example 1, the amount of water for injection was changed:

[0085] In Example 1, the prescribed dosage of water for injection was 1.5 mL.

[0086] Method 1: The volume of water for injection is 1.8 mL;

[0087] Method 2: The volume of water for injection is 2.0 mL;

[0088] Method 3: The volume of water for injection is 1.0 mL;

[0089] Method 4: The volume of water for injection is 1.2 mL;

[0090] The preparation, filtration and filling steps and methods are the same as in Example 1. The freeze-drying process is adjusted as needed according to the freezing condition of the sample to freeze the sample into shape.

[0091] Example 4: Selection of pH of intermediate drug solution during preparation

[0092] Referring to the formulation and preparation process of Example 1, the pH of the intermediate drug solution was changed during the preparation process:

[0093] In Example 1, the pH of the intermediate drug solution during preparation was 10.8;

[0094] Method 1: The pH of the intermediate drug solution is 10.2;

[0095] Method 2: The pH of the intermediate drug solution is 10.5;

[0096] Method 3: The pH of the intermediate drug solution is 11.1;

[0097] Method 4: The pH of the intermediate drug solution is 11.4;

[0098] The other steps and methods are the same as in Example 1.

[0099] Example 5: Selection of EDTA dosage

[0100] Referring to the formulation and preparation process of Example 1, the dosage of EDTA was changed:

[0101] Example 1: Prescribed dosage of EDTA 2.25 mg;

[0102] Method 1: The prescribed dosage of EDTA is 5.0 mg;

[0103] Method 2: The prescribed dosage of EDTA is 1.8 mg;

[0104] Method 3: The prescribed dosage of EDTA is 2.0 mg;

[0105] The other steps and methods are the same as in Example 1.

[0106] Example 6: Prescription content of omeprazole sodium

[0107] Referring to the formulation and preparation process of Example 1, the dosage of omeprazole sodium and the dosage of water for injection were changed:

[0108] In Example 1, the prescribed dosage of omeprazole sodium was 60 mg, and the dosage of water for injection was 1.5 mL.

[0109] Method 1: The prescribed dosage of omeprazole sodium is 40 mg, and the dosage of water for injection is 1.5 mL;

[0110] Method 2: The prescribed dosage of omeprazole sodium is 90 mg, and the dosage of water for injection is 2.0 mL;

[0111] The other steps and methods are the same as in Example 1.

[0112] Comparative Example 1:

[0113] The main difference from Example 1 is that in Comparative Example 1, 0.1% activated carbon was added after omeprazole sodium was dissolved during the preparation of the drug solution, while no activated carbon was added in this application.

[0114] Comparative Example 1:

[0115] Drug solution preparation: Add EDTA to 80% of the prescribed amount of water for injection (water temperature controlled at ≤26℃), stir to dissolve, add omeprazole sodium, stir to dissolve, add 0.1% activated carbon, stir to adsorb for 30 min, then adjust the pH with 2 mol / L sodium hydroxide to obtain a pH between 10.5 and 11.1, then add water for injection to complete the solution, and the final concentration is obtained.

[0116] The other methods and steps are the same as in Example 1.

[0117] Table 4. Control conditions for the preparation process

[0118]

[0119]

[0120] Results Analysis

[0121] 1. Effects of the number of stoppering cycles and residual oxygen content on formulation stability

[0122] The stability of drug tablets was evaluated by determining the content of various impurities in lyophilized powder injections obtained with different numbers of stoppering attempts and residual oxygen levels. We found that the number of stoppering attempts and residual oxygen levels significantly affected the impurity content and stability of the formulation. Compared to stoppering only once with residual oxygen controlled to ≤0.65% and stoppering twice without controlling residual oxygen to ≤0.65%, the stoppering process using two attempts with residual oxygen controlled to ≤0.65% ensured the stability of the formulation over a longer period and extended its shelf life. Details are as follows:

[0123] Lyophilized powder injections obtained by controlling different number of plugging cycles and residual oxygen content:

[0124] Example 1: Two compression tests were performed to control residual oxygen ≤0.65%;

[0125] Example 2, Method 1: One plugging operation, controlling residual oxygen ≤0.65%;

[0126] Example 2, Method 2: Two compressions, without controlling residual oxygen ≤0.65% (residual oxygen content higher than 0.65%);

[0127] Impurity content analysis was performed on the obtained lyophilized powder injection at 20℃ for 3 months, 6 months, 12 months, 24 months, and 36 months. The results were compared with the residual oxygen content and impurity content at 0 days, as shown in the table below. Among them, the known impurity is impurity D, whose chemical name is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole, and its structural formula is:

[0128]

[0129] Table 5. Residual oxygen content and impurity content of the formulations at different times under 20℃ conditions.

[0130]

[0131]

[0132] " / " indicates not involved, and "ND" indicates not detected.

[0133] in conclusion:

[0134] In Example 1, the stoppering process was performed twice, and the residual oxygen was controlled to be ≤0.65%. The resulting lyophilized powder injection, due to its good sealing and low residual oxygen content in the vial, maintained a residual oxygen level of <0.65% for 36 months. It was not easily oxidized to produce impurities D, and the content remained basically unchanged at around 0.02%, which was significantly lower than the impurity limit (≤0.5%). The total impurity content showed a gradual upward trend over 36 months, with the highest content being 0.57%, an increase of 0.48%, which was still significantly lower than the impurity limit (≤1.5%). It exhibited good stability over a long period of 36 months, thus extending its shelf life.

[0135] In Example 2, Method 1 involved only one stoppering process with residual oxygen controlled to ≤0.65%. Although this simplified the operation, it resulted in insufficient sealing. By March, residual oxygen exceeded 0.65%, making it highly susceptible to oxidation and generating impurity D. The content of impurity D increased significantly to 0.92%, which was significantly higher than the impurity limit (≤0.5%), leading to reduced product stability. The total impurity content showed a significant upward trend over 36 months, reaching 1.76% at 36 months, which was significantly higher than the impurity limit (≤1.5%). This prolonged period of stability over 36 months failed to meet the formulation standards.

[0136] In Example 2, during the stoppering process of Method 2, the residual oxygen was not controlled to be ≤0.65% after two stopperings. However, due to the two stopperings, the residual oxygen content increased slightly, but not significantly. Within 0 to 36 months, residual oxygen >0.65% was easily oxidized to produce impurity D, the content of which gradually increased. At 36 months, the content of impurity D was 0.42%, close to the impurity limit of 0.5%, significantly higher than that of impurity D in Example 1, and 14 times the content in Example 1. The total impurity content showed a significant upward trend within 36 months, reaching 1.26% at 36 months, close to the impurity limit of 1.5%, significantly higher than that of the total impurity content in Example 1, and 2.2 times the content in Example 1. The stability was poor over the long period of 36 months, failing to meet the formulation standards.

[0137] summary:

[0138] Examples 1 and 2, using methods 1-2 to control the number of stoppering cycles and residual oxygen during the stoppering process, show that the number of stoppering cycles and residual oxygen significantly affect the stability of the formulation.

[0139] Compared to the stoppering process with only one stoppering and residual oxygen ≤0.65% and the stoppering process with two stoppers without controlling residual oxygen ≤0.65%, only by stopping the stopper twice during the stoppering process and controlling residual oxygen ≤0.65% (e.g., Example 1) can the stability of the resulting formulation be guaranteed over a long period of 36 months, thus extending the shelf life of the lyophilized powder for injection be guaranteed by strictly controlling the residual oxygen content ≤0.65% while enhancing the sealing performance.

[0140] Conversely, formulations obtained using other methods for controlling the number of plugging cycles and residual oxygen content (e.g., methods 1-2 in Example 2) exhibit poor stability over a long period of 36 months, failing to meet formulation standards and thus unsuitable for use as qualified formulations.

[0141] 2. Effects of water for injection usage on finished product quality and energy consumption during the preparation process.

[0142] Analysis of the finished product quality and energy consumption of lyophilized powder injections obtained with different amounts of water for injection revealed that the amount of water for injection significantly affects the properties of the formulation and energy consumption. Compared to other amounts of water for injection, lyophilized powder injections prepared with 1.5–2.0 mL of water for injection meet the formulation standards. Specifically, lyophilized powder injections using 1.5 mL of water for injection significantly shorten the lyophilization time and reduce production costs. Details are as follows:

[0143] Lyophilized powder injections obtained from different types of water for injection:

[0144] Example 1: The volume of water for injection was 1.5 mL;

[0145] Example 3, Method 1: The volume of water for injection was 1.8 mL;

[0146] Example 3, Method 2: The volume of water for injection was 2.0 mL;

[0147] Example 3, Method 3: The volume of water for injection was 1.0 mL;

[0148] Example 3, Method 4: The volume of water for injection was 1.2 mL;

[0149] The effects of water for injection dosage on the finished product properties, reconstitution time, and lyophilization time (energy consumption) were analyzed comparatively, and the results are shown in the table below:

[0150] Table 6. Evaluation of Finished Product Quality and Energy Consumption

[0151]

[0152] in conclusion:

[0153] like Figure 1 As shown, in Example 1, lyophilized powder for injection was prepared using 1.5 mL of water for injection. The powder was white, loose, and lumpy with good properties. The reconstitution time was 15 s, which is short and the solubility was good. The total time required for lyophilization was 19.5 h, which is low in energy consumption.

[0154] In Example 3, Method 1 used 1.8 mL of water for injection to prepare lyophilized powder for injection. The powder was white, loose, and lumpy with good properties. The reconstitution time was 13 seconds, indicating good solubility and a short required reconstitution time. However, the total time required for lyophilization was 32 hours, and the energy consumption was increased by 164% compared to Example 1, significantly increasing production costs.

[0155] In Example 3, Method 2 used 2.0 mL of water for injection to prepare lyophilized powder for injection. The powder was white, loose, and lumpy with good properties. The reconstitution time was 13 seconds, indicating good solubility and a short required reconstitution time. However, the total time required for lyophilization was 45 hours, and the energy consumption was 230% of that in Example 1, significantly increasing production costs.

[0156] Example 3, Method 3: The lyophilized powder for injection was prepared using 1.0 mL of water for injection. The total time required for lyophilization was 15 hours, and the energy consumption was low. However, the product was a yellow block, which was not good in appearance. Moreover, the reconstitution time was 108 seconds, indicating poor solubility and a long reconstitution time. This caused hemolysis during clinical use and did not meet the formulation standards.

[0157] In Example 3 and Method 4, lyophilized powder for injection was prepared using 1.2 mL of water for injection. The total time required for lyophilization was 18 hours, and the energy consumption was low. However, the product was a light yellow, loose, lumpy substance with poor appearance. Furthermore, the reconstitution time was 80 seconds, indicating poor solubility and a long reconstitution time. This resulted in hemolysis during clinical use and did not meet the formulation standards.

[0158] summary:

[0159] Examples 1 and 3, methods 1-4, used different amounts of water for injection to prepare lyophilized powder injections, showing that the amount of water for injection significantly affects the properties of the formulation and the amount of energy consumed.

[0160] Compared to other dosages of water for injection, when 1.5–2.0 mL of water for injection is used to prepare lyophilized powder injections, the properties are good, the solubility is good, and the formulation meets the standards. The energy consumption increases with the increase of the amount of water for injection.

[0161] Among them, the lyophilized powder injection using 1.5 mL of water for injection (e.g., Example 1) has good properties, good solubility, the shortest lyophilization time, and the lowest energy consumption, which can reduce production costs and save energy while ensuring product quality.

[0162] Conversely, formulations obtained using other amounts of water for injection (e.g., methods 3-4 in Example 3) have poor properties and solubility and do not meet formulation standards.

[0163] 3. The effect of solution pH on formulation stability during preparation

[0164] The stability of the drug tablets was evaluated by determining the content of various impurities in lyophilized powder injections obtained from intermediate solutions at different pH values. We found that the pH of the preparation solution significantly affects the stability of both the intermediate solution and the formulation. Compared to other pH values, the lyophilized powder injections exhibited good stability and met formulation standards when the pH was between 10.5 and 11.1. Among these, the intermediate and formulation showed the best stability at pH 10.8. Details are as follows:

[0165] Lyophilized powder injections obtained from different intermediate drug solutions at different pH values:

[0166] Example 1: pH 10.8;

[0167] Example 4, Method 1: pH 10.2;

[0168] Example 4, Method 2: pH 10.5;

[0169] Example 4, Method 3: pH 11.1;

[0170] Example 4, Method 4: pH 11.4;

[0171] The stability of the drug solution was analyzed over 30 days at 60℃, and compared with the mass of the intermediate solution on day 0. The results are shown in the table below. The known impurity is impurity D, with the chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonyl]-1H-benzimidazole, and its structural formula is:

[0172]

[0173] Table 7. Stability of intermediate drug solutions under different pH conditions

[0174]

[0175] Note: "No precipitation" indicates that the intermediate is stable and the stabilization time meets the requirements for drug preparation.

[0176] Table 8. Impurity content of lyophilized powder injections prepared with different intermediate drug solutions at different pH values.

[0177]

[0178]

[0179] " / " indicates not involved, and "ND" indicates not detected.

[0180] in conclusion:

[0181] In Example 1, the intermediate solution was prepared at a pH of 10.8. No precipitation occurred within 22 hours, meeting the requirements for drug preparation and demonstrating good stability. The lyophilized powder for injection remained a white, loose, lumpy substance after 30 days, exhibiting good properties. The impurity D content increased by 0.03%, far below the impurity D limit standard (<0.5%). The total impurity content was 1.12%, below the total impurity limit standard (<1.5%), with no change in the number of impurities, indicating good stability.

[0182] In Example 4, the intermediate drug solution prepared using Method 1 had a pH of 10.2. The intermediate precipitated within 30 minutes, and the intermediate drug solution was in a suspended state, which did not meet the requirements for drug preparation and showed poor stability. After 30 days of storage, the lyophilized powder injection was a white, loose, lumpy substance with good properties. The content of impurity D increased by 0.18%, which was 0.15% higher than in Example 1, but was still lower than the limit standard for impurity D (<0.5%). The total impurity content was 2.98%, which increased by 2.83% and was significantly higher than the limit standard for total impurities (<1.5%). The number of impurities increased significantly by 4, indicating poor stability and failure to meet the formulation standards.

[0183] In Example 4, the preparation process of Method 2 used a drug solution with a pH of 10.5. No intermediates precipitated within 22 hours, meeting the requirements for drug preparation and demonstrating good stability. After 30 days of storage, the lyophilized powder injection was a light yellow, loose, lumpy substance with poor properties. The content of impurity D increased by 0.03%, far below the limit standard for impurity D (<0.5%). The total impurity content was 1.23%, below the limit standard for total impurities (<1.5%), and the number of impurities remained unchanged, indicating good stability.

[0184] In Example 4, the preparation process of Method 3 used a drug solution with a pH of 11.1. No intermediates precipitated within 22 hours, meeting the requirements for drug preparation and demonstrating good stability. After 30 days of storage, the lyophilized powder injections were all white, loose, lumpy substances with good properties. The content of impurity D increased by 0.03%, far below the limit standard for impurity D (<0.5%). The total impurity content was 1.29%, lower than the total impurity limit standard (<1.5%), and the number of impurities remained unchanged, indicating good stability.

[0185] In Example 4, the preparation process using a solution pH of 11.4 resulted in no precipitation of the intermediate within 22 hours, meeting the requirements for drug formulation and demonstrating good stability. However, after the preparation of the lyophilized powder injection, the total impurity content was significantly increased, by 0.14% compared to Example 1, and the number of impurities increased by 2 compared to Example 1. After 30 days of storage, it turned into a light yellow, loose, lumpy substance with poor properties. The content of impurity D increased by 0.20%, by 0.17% compared to Example 1, which is far below the limit standard for impurity D (<0.5%). The total impurity content was 3.54%, an increase of 3.31%, significantly higher than the total impurity limit standard (<1.5%), and the number of impurities increased significantly by 5, indicating poor stability and failure to meet the formulation standards.

[0186] summary:

[0187] Examples 1 and 4, methods 1-5, used different pH values ​​of intermediate drug solutions to prepare lyophilized powder injections, indicating that pH significantly affects the stability of intermediate drug solutions and formulations;

[0188] Compared to the pH of other intermediate drug solutions, the lyophilized powder injection exhibits good stability when the pH is adjusted to 10.5–11.1, meeting the formulation standards.

[0189] Among them, when the pH of the intermediate solution is 10.8 (for example, Example 1), the intermediate has good stability and the content and number of impurities are the lowest after being placed at 60°C for 30 days, indicating the best stability.

[0190] Conversely, formulations obtained using other pH values ​​(e.g., methods 1 and 4 in Example 4) exhibit poor stability and do not meet formulation standards, thus rendering them unsuitable for use as qualified products.

[0191] 4. Effect of EDTA dosage on formulation stability

[0192] The stability of the drug tablets was evaluated by determining the content of various impurities in lyophilized powder injections obtained with different EDTA dosages. We found that the EDTA dosage significantly affected the stability of the solution after preparation and storage in clinical practice. Compared to other EDTA dosages, using EDTA ≥2.25 mg resulted in good stability, meeting the formulation standards. The lowest EDTA dosage of 2.25 mg showed good color, appearance, and stability, indicating high safety. Details are as follows:

[0193] Lyophilized powder injections obtained with different EDTA dosages:

[0194] Example 1: The dosage of EDTA was 2.25 mg;

[0195] Example 5, Method 1: The dosage of EDTA was 5.0 mg;

[0196] Example 5, Method 2: EDTA dosage was 1.8 mg;

[0197] Example 5, Method 3: The dosage of EDTA was 2.0 mg;

[0198] The stability of the obtained lyophilized powder injection was simulated during the clinical solution preparation and storage process. The stability of the drug solution after 15 hours of storage was analyzed and compared with the stability of the drug solution after 0 hours of storage. The results are shown in the table below. Among them, the known impurity is impurity D, whose chemical name is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole, and its structural formula is:

[0199]

[0200] Table 9 shows the stability of the drug solution after 0 hours of storage in simulated clinical settings.

[0201]

[0202] " / " indicates not involved, and "ND" indicates not detected.

[0203] Table 10 shows the stability of the drug solution during the 15-hour storage period after preparation in a simulated clinical setting.

[0204]

[0205]

[0206] " / " indicates not involved, and "ND" indicates not detected.

[0207] in conclusion:

[0208] like Figure 2 As shown, in Example 1, 2.25 mg of EDTA was used. Compared with the solution that had been left to stand for 0 hours, after 15 hours, the solution became clear, and the absorbance at a wavelength of 440 nm increased by 0.002, which was less than 0.1. The color properties were good. The number of insoluble particles ≥10 μm was less than 6000, and the number of insoluble particles ≥25 μm was less than 600. The content of impurity D remained unchanged at 0.02%, which was far below the limit standard for impurity D (<0.5%). The content of other single impurities was 0.13%, which was far below the limit standard for other single impurities (<0.2%). The total impurity content increased to 0.34%, which was far below the limit standard for total impurities (<1.5%). The number of impurities increased by one. Clinically, the solution showed good stability within 15 hours after preparation.

[0209] In Example 5, Method 1 used 5.0 mg of EDTA. Compared with the solution that had been left to stand for 0 hours, after 15 hours, the solution became clear, and the absorbance at a wavelength of 440 nm was 0.065, an increase of 0.061, but less than 0.1. Its color and properties were good. The number of insoluble particles ≥10 μm was less than 6000, and the number of insoluble particles ≥25 μm was less than 600. The impurity D content remained unchanged at 0.02%, far below the impurity D limit standard (<0.5%). The content of other single impurities was 0.18%, higher than the other single impurity limit standard (<0.2%). The total impurity content was 0.52%, close to that of Example 1, but far below the total impurity limit standard (<1.5%). The number of impurities increased by one. Clinically, the solution showed good stability within 15 hours after preparation.

[0210] In Example 5, Method 2 used 1.8 mg of EDTA. Compared to the solution that had been left to stand for 0 hours, after 15 hours, the solution became clear, and the absorbance at 440 nm was 0.102, which is greater than 0.1, indicating poor color properties. The number of insoluble particles ≥10 μm was less than 6000, and the number of insoluble particles ≥25 μm was less than 600. The impurity D content remained unchanged at 0.02%, which is far below the impurity D limit standard (<0.5%). The content of other single impurities was 0.43%, which is higher than the limit standard of other single impurities (<0.2%). The total impurity content was 0.89%, which is lower than the total impurity limit standard (<1.5%), an increase of 0.4% compared to Example 1. The number of impurities increased by 6. Clinically, the stability of the solution after preparation within 15 hours is poor and does not meet the formulation standards.

[0211] In Example 5, Method 3 used 2.0 mg of EDTA. Compared to the solution that had been left to stand for 0 hours, after 15 hours, the solution became clear, and the absorbance at 440 nm was 0.112, which is greater than 0.1, indicating poor color properties. The number of insoluble particles ≥10 μm was less than 6000, and the number of insoluble particles ≥25 μm was less than 600. The impurity D content remained unchanged at 0.02%, which is far below the impurity D limit standard (<0.5%). The content of other single impurities was 0.47%, which is higher than the limit standard for other single impurities (<0.2%). The total impurity content was 0.96%, which is lower than the total impurity limit standard (<1.5%), an increase of 0.47% compared to Example 1. The number of impurities increased by 9. Clinically, the stability of the solution after preparation within 15 hours is poor and does not meet the formulation standards.

[0212] summary:

[0213] Examples 1 and 5, using methods 1-5, prepared lyophilized powder injections with different amounts of EDTA, demonstrating that the amount of EDTA significantly affects the stability of the solution after preparation and storage in clinical practice; compared with other amounts of EDTA, an amount of EDTA ≥2.25 mg resulted in good color and appearance, low impurity content and number, and good stability.

[0214] Among them, the lowest EDTA dosage of 2.25 mg proposed for the first time in this application (e.g., Example 1) has good color properties, the lowest impurity content and number, and good stability.

[0215] Conversely, formulations obtained using EDTA dosages (e.g., methods 2-3 in Example 5) exhibit poor stability and do not meet formulation standards, thus rendering them unsuitable for use as qualified products.

[0216] 5. The effect of activated carbon on formulation stability

[0217] Compared with the formulation obtained without activated carbon in the comparative example, the content of various impurities was determined to evaluate the stability of the drug tablets. We found that the addition of activated carbon significantly affected the stability of the formulation; compared with the preparation process of Comparative Example 1, the lyophilized powder injection prepared in Example 1 without the addition of activated carbon enhanced product stability and extended shelf life. Details are as follows:

[0218] For lyophilized powder injections obtained with and without activated carbon in the preparation process:

[0219] Example 1: No activated carbon added;

[0220] Comparative Example 1: Add 0.1% activated carbon;

[0221] The stability of the obtained lyophilized powder injection at 20℃ for extended periods (0 days, 3 months, 6 months, 12 months, 24 months, and 36 months) was analyzed for impurity content. The results are shown in the table below. 1-2. Experimental Procedure: The known impurity is impurity D, with the chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonyl]-1H-benzimidazole, and its structural formula is:

[0222]

[0223] Table 11 Residual oxygen content and impurity content of the formulation at 20℃ over a long period of time

[0224]

[0225] " / " indicates not involved, and "ND" indicates not detected.

[0226] in conclusion:

[0227] Example 1 shows that the lyophilized powder injection prepared by macromolecular adsorption without the addition of activated carbon during the solution preparation process maintained a relatively constant impurity D content of approximately 0.02% over 36 months, significantly lower than the impurity limit (≤0.5%). Other single impurities remained low and undetectable over the long term. The total impurity content showed a gradual upward trend over 36 months, reaching a maximum of 0.57%, an increase of 0.49%, all significantly lower than the impurity limit (≤1.5%). The number of impurities was low and remained constant over the long term, ensuring the stability of the omeprazole sodium lyophilized powder injection over a long period of 36 months and extending its shelf life.

[0228] The lyophilized powder injection prepared by adding 0.1% activated carbon to Comparative Example 1 showed an increasing trend in impurity D content over 36 months. Within 36 months, the impurity D content was below 0.10%, which is below the impurity limit of 0.5%. However, from March to 36 months, the impurity D content was higher than that of Example 1. The content of other single impurities was approximately 0.03%, significantly higher than that of Example 1. The total impurity content showed a significant increasing trend over 36 months, reaching 0.64% at 36 months, below the impurity limit of 1.5%, an increase of 0.07% compared to Example 1. The number of impurities was 7, a significant increase of 4 compared to Example 1, indicating the presence of unknown impurities and reduced product safety. The product exhibited poor stability over the long period of 36 months and did not meet the formulation standards.

[0229] summary:

[0230] The preparation of lyophilized powder injections in Example 1 and Comparative Example 1 with and without activated carbon showed that the addition of activated carbon significantly affected the stability of the formulation.

[0231] Compared with the preparation process of Comparative Example 1, the lyophilized powder injection prepared without the addition of activated carbon (e.g., Example 1) simplifies the preparation process, avoids the introduction of other impurities and contamination of clean areas and air conditioning systems, significantly enhances product stability, and extends shelf life.

[0232] 5. Comparison between this application and existing patents

[0233] Comparison document 1: CN104666255A;

[0234] Comparison document 2: CN103169674A;

[0235] Comparison document 3: CN102151264A;

[0236] Comparison document 4: CN109984998B;

[0237] Comparison document 5: CN112807282A;

[0238]

[0239] in conclusion:

[0240] Based on different omeprazole sodium contents, in Example 1 (60 mg omeprazole sodium) and Method 1 (40 mg omeprazole sodium) and Method 2 (90 mg omeprazole sodium) of Example 6, double-stopping was used and residual oxygen was controlled to be ≤0.65. The resulting lyophilized powder injection showed good stability and extended shelf life at 20°C for up to 36 months. Based on 60 parts by weight of omeprazole sodium, with 1.5 mL of water for injection, the lyophilization time was 19.5 h. When the omeprazole sodium content was changed to 40 mg or 90 mg, the lyophilization time was 19.5 h and 19.7 h, respectively. From the above data, it can be seen that the lyophilization time of this application is significantly shortened, greatly reducing production costs; and without the addition of antioxidants, the preparation process is simplified, with strong safety, and can be directly applied clinically; the absence of activated carbon to adsorb the pyrogen source makes the process simple and pollution-free.

[0241] Comparative document 1, based on 40 parts by weight of omeprazole sodium, uses 2.0 parts by volume of water for injection and has a freeze-drying time of 33 hours, which is 69% more than Example 1 of this application, greatly increasing production costs; the formulation adds activated carbon to adsorb heat sources, the process is complex, it is easy to cause pollution, and the safety is poor.

[0242] Comparative document 2, based on 40 parts by weight of omeprazole sodium, uses 2.0 parts by volume of water for injection and has a freeze-drying time of 33 hours, which is 69% more than Example 1 of this application, greatly increasing production costs; the formulation adds methionine, making the process complex; the formulation adds activated carbon to adsorb heat sources, making the process complex, prone to pollution, and with poor safety.

[0243] Reference document 3 only used a single stoppering and did not control residual oxygen. The resulting lyophilized powder injection had good stability within 9 months at 20°C, but the shelf life was significantly shortened to 25% of that in Example 1 of this application, and the stability was greatly reduced.

[0244] Comparative document 4 uses only one-time stoppering and does not control residual oxygen. The resulting lyophilized powder injection has good stability within 6 months at 20°C, but the shelf life is significantly shortened to less than 16.7% of that of this application, and the stability is greatly reduced. Based on 40 parts by weight of omeprazole sodium, the amount of water for injection is 1.8 parts by volume, and the lyophilization time is 26 hours, which is 33% more than that of Example 1 of this application, greatly increasing the production cost. The formulation adds activated carbon to adsorb the heat source, the process is complicated, and it is easy to cause pollution. The stability and safety are significantly reduced.

[0245] Comparative document 5 uses only one-time stoppering and does not control residual oxygen. The resulting lyophilized powder injection has good stability within 6 months at 20°C, but the shelf life is significantly shortened to less than 16.7% of that in Example 1 of this application, indicating a significant decrease in stability. Based on 40 parts by weight of omeprazole sodium, the amount of water for injection is 1.0 to 1.8 parts by volume, and the lyophilization time is 23 to 29 hours, which is significantly increased by 18 to 49% compared to Example 1 of this application, resulting in a significant increase in energy consumption. The addition of the antioxidant sodium bisulfite complicates the preparation process, and the antioxidant has strong chemical activity, leading to high risks and poor safety in subsequent clinical use. The addition of activated carbon to adsorb heat sources in the formulation complicates the process and is prone to contamination. Stability and safety are significantly reduced.

[0246] In summary, the lyophilized omeprazole sodium injection product produced using the technical solution of this invention has significant advantages in stability, safety, and cost-effectiveness compared to the formulations prepared by the prior art represented by Comparative Examples 1-5. It is a lyophilized powder injection with multiple advantages, including significantly improved stability, greatly shortened lyophilization time, and significantly enhanced safety, and can be directly used in clinical practice.

[0247] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A lyophilized omeprazole sodium injection, comprising omeprazole sodium, disodium ethylenediaminetetraacetate (EDTA), and sodium hydroxide; wherein water for injection is also added during the preparation of the lyophilized powder injection; the preparation process of the lyophilized powder injection requires secondary stoppering of the lyophilized sample and nitrogen purging to control the residual oxygen content ≤0.65%; the amount of water for injection added to every 40-90 parts by weight of the omeprazole sodium is 1.5 parts by volume; the amount of EDTA is ≥2.25 parts by weight; wherein, The correspondence between parts by weight and parts by volume is mg: mL; The lyophilized powder injection is prepared by a method comprising the following steps: (1) Preparation of drug solution: Dissolve omeprazole sodium and EDTA in water for injection; the volume of water for injection shall be 75-80% of the total volume. (2) Adjust pH: Adjust the pH of the solution to 10.5~11.1, then add water for injection, and filter to obtain the filtrate; (3) Sample freeze-drying: The filtrate is filled, pre-frozen, freeze-dried, and desorption-dryed, and then stoppered to obtain freeze-dried samples; (4) After the freeze-dried sample is filled with nitrogen to a pressure of -120~-80mbar, it is first plugged; then the second plugging is performed to control the residual oxygen content ≤0.65%, and the freeze-dried powder injection is obtained after being removed from the box and capped. The amount of water for injection is 1.5 mL, and the pre-freezing time is 1 hour.

2. The lyophilized powder injection according to claim 1, wherein, The omeprazole sodium is in the form of 40, 60, or 90 parts by weight.

3. The lyophilized powder injection according to claim 1, wherein, The amount of omeprazole sodium is 60 parts by weight.

4. A method for preparing lyophilized omeprazole sodium for injection according to any one of claims 1 to 3, comprising the following steps: (1) Preparation of drug solution: Dissolve omeprazole sodium and EDTA in water for injection; the volume of water for injection shall be 75-80% of the total volume. (2) Adjust pH: Adjust the pH of the solution, then add water for injection, and filter to obtain the filtrate; (3) Sample freeze-drying: The filtrate is filled, pre-frozen, freeze-dried, and desorption-dryed, and then stoppered to obtain freeze-dried samples; (4) After filling the freeze-dried sample with nitrogen to a pressure of -120~-80mbar, the first stopper is performed; then the second stopper is performed to control the residual oxygen content to ≤0.65%, and the freeze-dried powder injection is obtained after being removed from the box and capped.

5. The preparation method according to claim 4, wherein, In step (2), the pH is adjusted to 10.5~11.

1.

6. The preparation method according to claim 5, wherein, Adjust the pH to 10.

8.

7. The preparation method according to claim 4, wherein, The dissolution temperature in step (1) is 18~26℃.

8. The preparation method according to claim 7, wherein, The dissolution temperature in step (1) is 22℃.

9. The preparation method according to claim 4, wherein, The dissolution time in step (1) is <8h.

10. The preparation method according to claim 9, wherein, The dissolution time in step (1) is less than 30 minutes.

11. The preparation method according to claim 4, wherein, In step (3), The pre-freezing process involves pre-freezing at -45°C while maintaining a vacuum state. The freeze-drying process is as follows: freeze-dry at a temperature of -25℃ to 10℃, maintaining a vacuum of 0.16 to 0.20 mbar for 12 to 13 hours; The desorption drying process is as follows: at a temperature of 20℃~40℃, maintain a vacuum of 0.08~0.12mbar and desorb for 4.5~5.5h.

12. The preparation method according to claim 4, wherein, In step (2), the number of filtrations is 2 to 5; the filtration pressure is ≤5 bar. The filtration process uses polyethersulfone (PES) filter cartridges with a pore size of 0.22~0.45μm. During filtration, the pore size of the PES filter cartridge used later does not exceed the pore size of the PES filter cartridge used earlier.

13. The preparation method according to claim 12, wherein, In step (2), the filtration is performed 3 times; the filtration pressure is ≤3 bar.

14. The preparation method according to claim 4, wherein, The filtering is performed three times in step (2); First filtration: Under filtration pressure <3 bar, a 0.45 μm polyethersulfone filter cartridge is used to filter and obtain the filtrate; Second filtration: Under filtration pressure <3 bar, a 0.22 μm polyethersulfone filter cartridge is used to filter the filtrate that has completed the first filtration to obtain the filtrate. Third filtration: Under filtration pressure <3 bar, a 0.22 μm polyethersulfone filter cartridge is used to filter the filtrate that has completed the second filtration to obtain the filtrate.

15. The preparation method according to any one of claims 4 to 14, wherein, The lyophilized powder injection is administered via intravenous drip during drug treatment.

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