Diphenhydramine hydrochloride composition as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a diphenhydramine hydrochloride composition and a preparation method thereof. According to the diphenhydramine hydrochloride injection disclosed by the invention, the pH of the diphenhydramine hydrochloride solution is adjusted by adopting carbon dioxide, and terminal sterilization is performed on the diphenhydramine hydrochloride solution, so that the sterile guarantee level of the diphenhydramine hydrochloride injection is improved, and the clinical use safety is greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical preparations and relates to a method for preparing a diphenhydramine hydrochloride composition. More specifically, this invention relates to a diphenhydramine hydrochloride injection resistant to terminal sterilization and its preparation method. Background Technology

[0002] The original formulation of diphenhydramine hydrochloride injection was developed by McNeil Consultant Health Care and first marketed in 1947. It was primarily used to improve allergic reactions in the blood or plasma and to treat other simple, immediate allergic disorders, motion sickness, and Parkinson's syndrome. Currently, the original formulation has been withdrawn from the market. Diphenhydramine hydrochloride injection (1 mL: 50 mg), approved for marketing in the United States by West-Ward Pharmaceuticals International Ltd. in 1972, is listed by the FDA as a reference formulation for generic drugs. This drug is recognized internationally as an equivalent and is also included in the reference formulation list by the Center for Drug Evaluation (CDE) of the China Food and Drug Administration.

[0003] Due to its chemical structure, diphenhydramine hydrochloride is easily degraded in aqueous solution at high temperatures. Therefore, diphenhydramine hydrochloride injection solution is usually not terminally sterilized and is produced using aseptic filtration.

[0004] Ward Pharmaceuticals International Ltd's diphenhydramine hydrochloride injection (1 mL: 50 mg) has a pH of 4.0-6.5 and contains 100 micrograms of the antibacterial agent benzethonium chloride per vial. Moist heat sterilization of this company's diphenhydramine hydrochloride injection resulted in a significant increase in related substances after sterilization, indicating that the reference formulation is not resistant to moist heat sterilization and that the terminal sterilization process with the highest level of aseptic assurance was not selected for the reference formulation. Furthermore, although the benzethonium chloride in the reference formulation is present in low concentrations, it has clear cytotoxicity and poses potential drawbacks such as the possibility of allergic reactions in individual patients. Therefore, the use of benzethonium chloride in diphenhydramine hydrochloride injection in humans poses a potential safety risk.

[0005] Several diphenhydramine hydrochloride injection solutions have been approved for marketing in China, with a certain amount of benzyl alcohol added as a bacteriostatic agent to control sterility. Chen Li, in her article "Determination of Benzyl Alcohol Content in Diphenhydramine Hydrochloride Injection by High Performance Liquid Chromatography (Strait Pharmaceutical Journal, Vol. 25, December 2013, pp. 121-123)," also reported that "benzyl alcohol is often added to diphenhydramine injection as a bacteriostatic agent." The State Food and Drug Administration has also stipulated in its "Notice on Strengthening the Management of Benzyl Alcohol Injection" that if benzyl alcohol is present in the prescription or solvent, it should be clearly indicated in the instructions, and its use for intramuscular injection in children is prohibited. Therefore, the use of benzyl alcohol also poses certain risks to the clinical use of diphenhydramine hydrochloride injection.

[0006] Diphenhydramine hydrochloride has good solubility under acidic conditions, but it is easily hydrolyzed to form diphenylmethanol, which is poorly soluble in water. Through extensive experimentation, the inventors of this invention have discovered that the hydrolysis rate of diphenhydramine hydrochloride in aqueous solution is affected by temperature and pH levels. Diphenhydramine hydrochloride is difficult to withstand sterilization temperatures under relatively low acidity conditions. In existing technologies, diphenhydramine hydrochloride injection solutions degrade at high temperatures, producing impurities A (2-(diphenylmethoxy)-N-methylethylamine) and D (diphenylmethanol).

[0007] Through research, the inventors of this invention have also discovered that increasing the pH level can significantly improve the thermal stability of diphenhydramine hydrochloride injection. Therefore, raising the pH of the solution to a neutral or alkaline level could potentially make it resistant to moist heat sterilization. However, increasing the pH level significantly reduces the solubility of diphenhydramine hydrochloride, causing it to precipitate during room temperature preparation. Under existing formulations, adjusting the pH level cannot achieve terminal sterilization while ensuring the properties of the solution.

[0008] In summary, while diphenhydramine hydrochloride aqueous solution dissolves under acidic conditions, it cannot withstand terminal sterilization. Therefore, bacteriostatic agents are often added to ensure sterility. However, bacteriostatic agents generally have clear cytotoxicity, and although present in small amounts, they pose certain risks during clinical use. Furthermore, the use of bacteriostatic agents also carries the disadvantage of potentially causing allergic reactions in some patients, and it also affects drug accessibility for certain groups (such as children) in clinical practice.

[0009] In response to the above-mentioned situation, the present invention, through extensive experiments and verification, developed a formulation for diphenhydramine hydrochloride injection with fewer excipients. The production process is simple, terminal sterilization is possible, the product quality is stable, and the preparation method is suitable for large-scale production, greatly improving the safety for clinical use. Summary of the Invention

[0010] To address the shortcomings of existing technologies for diphenhydramine hydrochloride injection, which employ non-terminal sterilization aseptic processes and require the addition of bacteriostatic agents to ensure sterility, leading to a series of clinical safety risks, this invention provides a diphenhydramine hydrochloride composition and preparation method that can withstand terminal sterilization without the use of bacteriostatic agents. The diphenhydramine hydrochloride injection prepared by this invention not only achieves the highest level of sterility assurance but also exhibits superior product quality and stability compared to commercially available formulations, resulting in better clinical safety.

[0011] Through extensive exploratory experiments, the inventors of this invention discovered that carbon dioxide, a weakly acidic gas, dissolves in water to form carbonic acid, which can adjust the pH of the solution to a certain extent. Furthermore, the carbonic acid formed is easily decomposed back into CO2 and water upon heating. The inventors of this invention also found that, under specific conditions (such as a sealed environment), by using CO2 in conjunction with a specific pH adjuster to adjust the pH of an aqueous solution of diphenhydramine hydrochloride, the pH of the drug solution can be controlled to be at different pH levels at different temperatures—acidic at room temperature and neutral or alkaline at sterilization temperature.

[0012] The present invention aims to provide a diphenhydramine hydrochloride injection solution resistant to terminal sterilization and its preparation method, thereby improving the sterility assurance level of the product and enhancing its stability and safety.

[0013] This invention provides a diphenhydramine hydrochloride composition resistant to terminal sterilization, characterized in that the composition comprises diphenhydramine hydrochloride, a pH adjuster, water for injection, and a protective gas;

[0014] The protective gas is carbon dioxide (CO2); the pH of the solution of the composition is 5.5–6.5.

[0015] In some embodiments, the formulation of the above-described diphenhydramine hydrochloride composition may be:

[0016] Prescription composition Dosage diphenhydramine hydrochloride 50g pH adjuster Adjust the pH to 7.0–8.0. <![CDATA[CO2]]> Appropriate amount Water for Injection Add to 1000ml

[0017] The above prescription ratios can also be expressed as follows, and the two are essentially equivalent:

[0018] Prescription composition Prescription concentration (w / v) diphenhydramine hydrochloride 5％ Sodium hydroxide Adjust the pH to 7.0–8.0. carbon dioxide Appropriate amount Water for Injection Add to 100%

[0019] In other embodiments, the prescription composition may also be:

[0020] Prescription composition Dosage diphenhydramine hydrochloride 20g pH adjuster Adjust the pH to 7.0–8.0. <![CDATA[CO2]]> Appropriate amount Water for Injection Add to 1000ml

[0021] The CO2 dosage mentioned in the above prescription is described as "appropriate amount," meaning that CO2 exists in gaseous form. The actual dosage is difficult to calculate and should be determined based on the final target of the prescription process or its technical parameters. This does not imply an unclear range. In this invention, CO2 is used by introducing (blowing) CO2 into an aqueous solution through a suitable conduit, allowing it to dissolve in the water. A portion of the CO2 reacts with the water to form carbonic acid. Those skilled in the art will understand that when CO2 is introduced into the water, a considerable portion will inevitably escape without dissolving. The actual CO2 dosage depends on the flow rate, time, and temperature of the aeration. The actual dosage should be determined based on the final target of the prescription process or technical parameters. For example, the aeration can be stopped when the pH of the solution reaches the target value. In some embodiments of this invention, when preparing the diphenhydramine hydrochloride composition of the above prescription, the amount of CO2 used is to maintain the pH of the solution between 5.5 and 6.5.

[0022] In the diphenhydramine hydrochloride composition described above, the pH adjuster is selected from one or more of sodium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, NaOH, sodium carbonate, and sodium bicarbonate; preferably, the pH adjuster is selected from one or more of NaOH, sodium carbonate, and sodium bicarbonate; more preferably, the pH adjuster is selected from one or a combination of NaOH and sodium carbonate; even more preferably, the pH adjuster is selected from NaOH.

[0023] In some embodiments, when preparing the diphenhydramine hydrochloride composition with the above-mentioned formulation, it can be prepared according to the following method: For example, to prepare 1L of the above-mentioned diphenhydramine hydrochloride composition, first measure 600-800ml of water for injection, add diphenhydramine hydrochloride, stir and dissolve, add an aqueous solution of pH adjuster to adjust the pH to 7.0-8.0, and then pass carbon dioxide gas into the solution at 15-30°C until the solution is clear, and the final solution pH is 5.5-6.5.

[0024] In some embodiments, the diphenhydramine hydrochloride composition of the present invention does not contain any other excipients.

[0025] In some embodiments, the diphenhydramine hydrochloride composition of the present invention may also contain other pharmaceutically acceptable excipients that should not affect the quality of the diphenhydramine hydrochloride composition.

[0026] In some embodiments, the diphenhydramine hydrochloride composition with the above-described formulation can also be prepared according to the following steps, which are substantially equivalent to the preparation method of the diphenhydramine hydrochloride composition described above:

[0027] (1) Take 60% to 80% water for injection according to the prescription, control the water temperature at 15 to 30°C, add diphenhydramine hydrochloride, and stir until dissolved;

[0028] (2) Add an aqueous solution of sodium hydroxide dropwise to the solution to adjust the pH to 7.0–8.0;

[0029] (3) Control the solution temperature to 15-30℃, continuously introduce carbon dioxide gas until the solution is clear, and the final pH is 5.5-6.5;

[0030] (4) Add water for injection and bring the volume to full.

[0031] Furthermore, the diphenhydramine hydrochloride composition prepared by the above method can be further filled into glass vials and terminally sterilized using methods feasible in the art to prepare a sterilized diphenhydramine hydrochloride composition (i.e., diphenhydramine hydrochloride injection). The glass vials mentioned above refer to pharmaceutical packaging materials. In this invention, the glass vials are selected from ampoules or vials, preferably ampoules; ampoules and vials can be sealed by fusion sealing and stoppering, respectively. The methods for further filling and terminal sterilization described above are as follows:

[0032] (5) Fill the headspace of the glass bottle with protective gas and control the headspace oxygen <5%. Fill the glass bottle with the solution obtained in step (4) and seal the glass bottle immediately after filling.

[0033] (6) Moist heat sterilization, control the sterilization temperature at 121℃ and the sterilization time at 12-15 min, and the product is obtained.

[0034] Typically, the composition solution obtained in step (4) of the above preparation method should be filled and sterilized within a suitable time, usually controlled within 8 hours. If it is not filled for a longer period of time, the carbon dioxide present in the solution as carbonic acid will decompose and escape, thus increasing the pH of the solution and causing the dissolved diphenhydramine hydrochloride to precipitate as solid. If the solution has not been contaminated or deteriorated for other reasons, carbon dioxide can be introduced into the solution to redissolve the diphenhydramine hydrochloride and restore the pH of the solution to acidity.

[0035] In the filling and terminal sterilization methods described above, the filling of the glass bottle headspace with protective gas in step (5) refers to filling the glass bottle with protective gas using a filling needle.

[0036] Furthermore, the present invention provides a diphenhydramine hydrochloride injection solution, characterized in that the injection solution comprises diphenhydramine hydrochloride, a pH adjuster, water for injection, and CO2; the pH of the injection solution is 5.5 to 6.5;

[0037] The pH adjuster is selected from one or more of NaOH, sodium carbonate, and sodium bicarbonate; preferably, the pH adjuster is selected from one or a combination of NaOH and sodium carbonate; more preferably, the pH adjuster is selected from NaOH.

[0038] In some implementations, the specific prescription may be:

[0039] Prescription composition Dosage diphenhydramine hydrochloride 50g pH adjuster Adjust the pH to 7.0–8.0. <![CDATA[CO2]]> Appropriate amount Water for Injection Add to 1000ml

[0040] In other embodiments, the specific prescription may be:

[0041] Prescription composition Dosage diphenhydramine hydrochloride 20g pH adjuster Adjust the pH to 7.0–8.0. <![CDATA[CO2]]> Appropriate amount Water for Injection Add to 1000ml

[0042] The diphenhydramine hydrochloride injection solution described above can be prepared according to the following steps:

[0043] (1) Take 60% to 80% water for injection according to the prescription, control the water temperature at 15 to 30°C, add diphenhydramine hydrochloride, and stir until dissolved;

[0044] (2) Add an aqueous solution of pH adjuster to adjust the pH of the above solution to 7.0-8.0;

[0045] (3) Maintain the solution temperature at 15-30℃, continuously introduce CO2 gas until the solution is clear, and the final pH is 5.5-6.5;

[0046] (4) Add water for injection and bring the volume to full;

[0047] (5) Fill the headspace of the glass bottle with protective gas (use a filling needle to fill the glass bottle with protective gas), control the headspace oxygen <5%, fill the glass bottle with the solution obtained in step (4), and seal the glass bottle immediately after filling.

[0048] (6) Moist heat sterilization, control the sterilization temperature at 121℃ and the sterilization time at 12-15 min, and the product is obtained.

[0049] The concentration of the diphenhydramine hydrochloride composition or diphenhydramine hydrochloride injection described above can be 50 mg / ml or 20 mg / ml.

[0050] In this invention, the terms "containing" or "comprising" can be open-ended, semi-closed, or closed-ended. In other words, the terms also include "consisting of substantially" or "composed of".

[0051] In this invention, the term "pharmaceutically acceptable" means that, with respect to those compounds, materials, compositions and / or dosage forms, they are suitable for use in contact with human and animal tissues, within the limits of reliable medical judgment, without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0052] In this invention, the detection of impurities and their contents can be carried out by referring to the quality standards included in the 2020 edition of the Chinese Pharmacopoeia or by using optimized methods.

[0053] This invention overcomes the shortcomings of existing technologies where diphenhydramine hydrochloride injection is not resistant to terminal sterilization, and eliminates the need for bacteriostatic agents. This invention provides a diphenhydramine hydrochloride composition resistant to moist heat sterilization and its preparation method, achieving the highest level of sterility assurance, avoiding the use of bacteriostatic agents, and greatly improving the safety of clinical use. The formulation process of this invention is suitable for large-scale industrial production, and the quality and stability of the diphenhydramine hydrochloride injection produced are superior to the reference formulation. Attached Figure Description

[0054] none. Detailed Implementation

[0055] The technical solution of the present invention will now be further described with reference to specific embodiments. These embodiments are merely typical examples illustrating the present invention and do not constitute any limitation on the scope of the present invention. For those skilled in the art, it is neither necessary nor possible to exhaustively describe all implementation methods. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solution of the present invention can be made without departing from the spirit and scope of the present invention, but all such modifications and substitutions fall within the protection scope of the present invention. Experimental methods in the following embodiments that do not specify specific experimental conditions are generally performed under conventional conditions or according to the conditions recommended by the manufacturer.

[0056] Example 1:

[0057]

[0058]

[0059] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0060] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0061] (2) Add sodium hydroxide solution dropwise to adjust the pH of the above solution to 7.0;

[0062] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 5.5;

[0063] (4) Add water for injection and bring the volume to 100ml.

[0064] (5) Fill the headspace of the ampoule with CO2 (fill the ampoule with CO2 using a filling needle), control the headspace oxygen <5%, and seal it immediately after filling with the solution obtained in step (4).

[0065] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 12min.

[0066] Example 2

[0067] prescription composition diphenhydramine hydrochloride 5g Sodium bicarbonate Adjust the pH to 7.5. <![CDATA[CO2]]> Add an appropriate amount and adjust the final pH to 6.0. Water for Injection Add to 100ml

[0068] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0069] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0070] (2) Add sodium bicarbonate dropwise to adjust the pH of the above solution to 7.5;

[0071] (3) Maintain the solution temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 6.0;

[0072] (4) Add water for injection and bring the volume to 100ml.

[0073] (5) Fill the headspace of the ampoule with CO2 (fill the ampoule with CO2 using a filling needle), control the headspace oxygen <5%, and seal it immediately after filling with the solution obtained in step (4).

[0074] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 15min.

[0075] Example 3

[0076]

[0077]

[0078] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0079] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0080] (2) Add sodium hydroxide dropwise to adjust the pH of the above solution to 7.5;

[0081] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 6.5;

[0082] (4) Add water for injection and bring the volume to 100ml.

[0083] (5) Fill the headspace of the ampoule with CO2 (fill the ampoule with CO2 using a filling needle), control the headspace oxygen <5%, and seal it immediately after filling with the solution obtained in step (4).

[0084] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 12min.

[0085] Example 4

[0086] prescription composition diphenhydramine hydrochloride 5g Sodium hydroxide Adjust the pH to 8.0. <![CDATA[CO2]]> Add an appropriate amount and adjust the final pH to 6.5. Water for Injection Add to 100ml

[0087] The preparation method is the same as in Example 1.

[0088] Example 5

[0089] prescription composition diphenhydramine hydrochloride 5g Sodium hydroxide Adjust the pH to 7.5. <![CDATA[CO2]]> Add an appropriate amount and adjust the final pH to 6.0. Water for Injection Add to 100ml

[0090] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0091] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0092] (2) Add sodium hydroxide dropwise to adjust the pH of the above solution to 7.5;

[0093] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 6.0;

[0094] (4) Bring to full volume;

[0095] (5) The headspace of the ampoule is filled with CO2 to control the headspace oxygen <5%, and the ampoule is immediately sealed after being filled with the solution obtained in step (4).

[0096] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 15min.

[0097] Example 6

[0098] prescription composition diphenhydramine hydrochloride 5g Sodium carbonate Adjust the pH to 7.0. <![CDATA[CO2]]> Add an appropriate amount and adjust the final pH to 6.0. Water for Injection Add to 100ml

[0099] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0100] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0101] (2) Adjust the pH of the above solution to 7.0 by adding sodium carbonate solution dropwise;

[0102] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 6.0;

[0103] (4) Add water for injection and bring the volume to 100ml.

[0104] (5) Fill the headspace of the ampoule with CO2 (fill the ampoule with CO2 using a filling needle), control the headspace oxygen <5%, and seal it immediately after filling with the solution obtained in step (4).

[0105] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 15min.

[0106] Example 7

[0107] prescription composition diphenhydramine hydrochloride 5g Sodium bicarbonate Adjust the pH to 7.0. <![CDATA[CO2]]> Add an appropriate amount and adjust the final pH to 6.0. Water for Injection Add to 100ml

[0108] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0109] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0110] (2) Add sodium bicarbonate solution dropwise to adjust the pH of the above solution to 7.0;

[0111] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 6.0;

[0112] (4) Add water for injection and bring the volume to 100ml.

[0113] (5) Fill the headspace of the ampoule with CO2 (fill the ampoule with CO2 using a filling needle), control the headspace oxygen <5%, and seal it immediately after filling with the solution obtained in step (4).

[0114] (6) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 15min.

[0115] Comparative Example 1

[0116] It contains the following components:

[0117] Add 5% diphenhydramine hydrochloride, adjust the pH to 5.5 with sodium hydroxide, and add water for injection to 100% by volume;

[0118] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0119] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0120] (2) Add sodium hydroxide dropwise to adjust the pH of the above solution to 5.5;

[0121] (3) Bring to full volume;

[0122] (4) Control headspace oxygen <5% by N2 filling, and seal immediately after filling;

[0123] (5) Moist heat sterilization: control the sterilization temperature at 121℃ and the sterilization time at 12min.

[0124] Comparative Example 2

[0125] It contains the following components:

[0126] Add 5% diphenhydramine hydrochloride, adjust the pH to 6.5 with sodium hydroxide, and add water for injection to 100% by volume;

[0127] The preparation method is the same as that of Comparative Example 1.

[0128] Comparative Example 3

[0129] It contains the following components:

[0130] Add 5% diphenhydramine hydrochloride, adjust the pH to 7.0 with sodium hydroxide, and add water for injection to a volume of 100%.

[0131] The preparation method is the same as that of Comparative Example 1.

[0132] Comparative Example 4

[0133] It contains the following components:

[0134] Add 5% diphenhydramine hydrochloride, pre-adjust the pH to 7.0 with sodium hydroxide, adjust the final pH to 5.5 with CO2, and add water for injection to 100% volume.

[0135] The preparation of diphenhydramine hydrochloride injection according to the above proportions includes the following specific steps:

[0136] (1) Take 80% water for injection, control the water temperature at 25℃, add diphenhydramine hydrochloride, and stir until dissolved;

[0137] (2) Add sodium hydroxide dropwise to adjust the pH of the above solution to 7.0;

[0138] (3) Maintain the water temperature at 25°C and continuously introduce CO2 until the solution becomes clear and the final pH is 5.5;

[0139] (4) Bring to full volume;

[0140] (5) Control headspace oxygen <5% by CO2 filling and seal immediately after filling.

[0141] The reference formulation was subjected to moist heat sterilization at a temperature of 121°C for 12 minutes.

[0142] The properties, pH, related substances, and stability of each example, comparative example, reference preparation, and terminally sterilized reference preparation were examined (accelerated stability test conditions: 40℃±2℃, 75%±5%RH; long-term stability test conditions: 30℃±2℃, 65%±5%RH). Tables 1, 2, and 3 summarize the test results of different diphenhydramine hydrochloride injections at 0 days, 3 months (accelerated), and 6 months (long-term). The test methods can refer to the quality standards included in the 2020 edition of the Chinese Pharmacopoeia or use methods further optimized thereto.

[0143] Table 1

[0144]

[0145] Table 2

[0146]

[0147] Table 3

[0148]

[0149] The results showed that the quality of Examples 1-7 at day 0 was comparable to that of the commercially available formulation, and the accelerated stability was significantly better than that of the reference formulation, while the reference formulation showed a sharp increase in related substances after sterilization. The results of Comparative Examples 1-3 showed that increasing the pH could effectively reduce the increase of related substances after sterilization, but simply adjusting the pH with NaOH resulted in poor solution properties after the pH was raised to 7.0, although the solution could only withstand terminal sterilization after the pH was raised to 7.0. Compared with Examples 2 and 5, further extending the sterilization time did not result in an increase in related substances.

[0150] As can be seen from the above, after ensuring that the pH of the solution is initially adjusted to 7.0-8.0 with NaOH, the pH can be adjusted back to 5.5-6.5 with CO2, which can achieve terminal sterilization of the product and ensure good product properties and stability.

[0151] The present invention has been described above by way of example, but the present invention is not limited to the specific embodiments described above. Any modifications or variations made based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A diphenhydramine hydrochloride composition, characterized in that, The composition comprises diphenhydramine hydrochloride, a pH adjuster, water for injection, and a protective gas; wherein the protective gas is CO2; and the pH of the solution of the composition is 5.5–6.

5.

2. The diphenhydramine hydrochloride composition according to claim 1, characterized in that, The pH adjuster is selected from one or more of sodium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, NaOH, sodium carbonate, and sodium bicarbonate; preferably, the pH adjuster is selected from one or more of NaOH, sodium carbonate, and sodium bicarbonate; more preferably, the pH adjuster is selected from one or a combination of NaOH and sodium carbonate; even more preferably, the pH adjuster is selected from NaOH.

3. The diphenhydramine hydrochloride composition according to any one of claims 1-2, characterized in that, The formulation of the diphenhydramine hydrochloride composition is selected from: and 。 4. The diphenhydramine hydrochloride composition according to any one of claims 1-3, characterized in that, The diphenhydramine hydrochloride composition described herein does not contain any other excipients.

5. The diphenhydramine hydrochloride composition according to any one of claims 1-4, characterized in that, The composition is prepared according to the following steps: (1) Take 60% to 80% water for injection according to the prescription, control the water temperature at 15 to 30°C, add diphenhydramine hydrochloride, and stir until dissolved; (2) Add an aqueous solution of sodium hydroxide dropwise to the solution to adjust the pH to 7.0–8.0; (3) Control the water temperature to 15-30℃, continuously introduce CO2 gas until the solution is clear, and the final pH is 5.5-6.5; (4) Add water for injection and bring the volume to full.

6. The diphenhydramine hydrochloride composition according to claim 5, characterized in that, The preparation further includes the following steps: (5) Fill the headspace of the glass bottle with protective gas and control the headspace oxygen <5%. Fill the glass bottle with the solution obtained in step (4) and seal the glass bottle immediately after filling. (6) Moist heat sterilization, control the sterilization temperature at 121℃ and the sterilization time at 12-15 min, and the product is obtained.

7. A diphenhydramine hydrochloride injection solution, characterized in that, The injection solution is composed of diphenhydramine hydrochloride, pH adjuster, water for injection, and CO2; the pH of the injection solution is 5.5 to 6.

5.

8. The diphenhydramine hydrochloride injection solution according to claim 7, characterized in that, The pH adjuster is selected from one or more of NaOH, sodium carbonate, and sodium bicarbonate; preferably, the pH adjuster is selected from one or a combination of NaOH and sodium carbonate; more preferably, the pH adjuster is selected from NaOH.

9. The diphenhydramine hydrochloride injection solution according to any one of claims 7-8, characterized in that, The formulation of the injection solution is selected from... or 。 10. The diphenhydramine hydrochloride injection solution according to any one of claims 7-9, characterized in that, The injection solution is prepared according to the following steps: (1) Take 60% to 80% water for injection according to the prescription, control the water temperature at 15 to 30°C, add diphenhydramine hydrochloride, and stir until dissolved; (2) Add an aqueous solution of pH adjuster to adjust the pH of the above solution to 7.0-8.0; (3) Maintain the solution temperature at 15-30℃, continuously introduce CO2 gas until the solution is clear, and the final pH is 5.5-6.5; (4) Add water for injection and bring the volume to full; (5) Fill the headspace of the glass bottle with protective gas and control the headspace oxygen <5%. Fill the glass bottle with the solution obtained in step (4) and seal the glass bottle immediately after filling. (6) Moist heat sterilization, control the sterilization temperature at 121℃ and the sterilization time at 12-15 min, and the product is obtained.

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