Lidocaine hydrochloride injection and preparation method thereof

Abstract

The invention relates to a lidocaine hydrochloride injection and a preparation method thereof, and relates to the technical field of biological medicine manufacturing, and the preparation method of the lidocaine hydrochloride injection comprises the steps of liquid preparation, filtration, potting and sterilization. The solution preparation comprises the following steps: adding a pH regulator into the water for injection accounting for 75-80% vol of the prescription dosage, regulating the pH to 8.3-8.8, adding lidocaine hydrochloride accounting for the prescription dosage, stirring to obtain a first solution, and the like. Compared with the prior art, lidocaine hydrochloride is fed in a suitable alkalescent environment, so that the dissolving speed and the dissolving uniformity of raw material medicines are improved, meanwhile, the strategy also reduces the amplitude of follow-up pH regulation, the impact on a solution system is greatly reduced, and the preparation method is suitable for industrial production. And the whole liquid preparation process can be more slowly completed at room temperature, so that the quality stability of the lidocaine hydrochloride injection is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine manufacturing, in particular to a lidocaine hydrochloride injection and a preparation method thereof. BACKGROUND

[0002] Lidocaine hydrochloride is a classical drug widely used in clinical treatment, which has both local anesthetic and antiarrhythmic effects. In local anesthesia, it can effectively block the conduction of nerve impulses, providing reliable anesthetic effect for various surgical operations and pain treatment, and is widely used in small operations and diagnosis and treatment in departments such as stomatology, ophthalmology and surgery; in terms of antiarrhythmia, for arrhythmia caused by acute myocardial infarction, cardiac surgery, etc., lidocaine hydrochloride can quickly stabilize the membrane potential of myocardial cells and restore normal heart rhythm, and is one of the preferred drugs for the treatment of ventricular arrhythmia in clinic.

[0003] Lidocaine hydrochloride injection is a common dosage form of the drug, and its quality stability is directly related to the safety and effectiveness of clinical medication. In the existing preparation technology, the liquid preparation link is the key to the quality of the injection. At present, the conventional liquid preparation method is to dissolve lidocaine hydrochloride raw material containing a hydrochloride structure in neutral conditions in water for injection at a temperature higher than room temperature, form a strong acid solution, and then add a pH adjuster such as sodium hydroxide to make the system pH close to neutral. However, the quality stability of the injection prepared by this process is poor. However, the quality stability of the lidocaine hydrochloride injection obtained by the existing process is poor and needs to be further improved. SUMMARY

[0004] To solve the above problems, the present application provides a lidocaine hydrochloride injection and a preparation method thereof.

[0005] In a first aspect, the present application provides a preparation method of a lidocaine hydrochloride injection, which comprises liquid preparation, filtration, filling and sealing, and sterilization.

[0006] The liquid preparation comprises the following processes:

[0007] A pH adjuster is added to water for injection at 75-80% of the prescription amount, the pH is adjusted to 8.3-8.8, then the prescription amount of lidocaine hydrochloride is added and stirred to obtain a first solution;

[0008] A prescription amount of sodium chloride is added to the first solution and stirred to obtain a second solution;

[0009] The pH of the second solution is adjusted to 5.0-6.0 with a pH adjuster, then the remaining water for injection is added to the prescription amount and stirred to obtain a lidocaine hydrochloride solution;

[0010] The temperature of the water for injection is room temperature.

[0011] Further, the composition of the lidocaine hydrochloride injection solution includes, per 2.5 L of a prescription amount of the lidocaine hydrochloride injection solution:

[0012] lidocaine hydrochloride 49-51 g;

[0013] sodium chloride 14-16 g;

[0014] a pH adjuster in an appropriate amount;

[0015] water for injection is added to 2.5 L.

[0016] Further, the composition of the lidocaine hydrochloride injection solution includes, per 2.5 L of a prescription amount of the lidocaine hydrochloride injection solution:

[0017] lidocaine hydrochloride 50 g;

[0018] sodium chloride 15 g;

[0019] a pH adjuster in an appropriate amount;

[0020] water for injection is added to 2.5 L.

[0021] Further, the pH adjuster includes at least one of 0.1 mol / L aqueous sodium hydroxide solution and 0.1 mol / L aqueous hydrochloric acid solution.

[0022] Further, the filtration includes the following process: the lidocaine hydrochloride solution is sequentially filtered through a 0.45 μm polyether sulfone microporous filter and a 0.22 μm polyether sulfone microporous filter.

[0023] Further, the filling work condition parameter includes that the filling bottle includes at least one of a transparent glass ampoule and a polyethylene ampoule, and the single filling amount is 5.1-5.3 ml.

[0024] Further, the sterilization work condition parameter includes that the temperature is 120-122°C and the time is 15 minutes.

[0025] Further, the preparation method of the lidocaine hydrochloride injection solution further includes leak detection, lamp inspection, and packaging.

[0026] In a second aspect, based on the same inventive concept, the present application provides a lidocaine hydrochloride injection solution prepared by the preparation method of the lidocaine hydrochloride injection solution according to any one of the first aspect.

[0027] Further, the lidocaine hydrochloride injection solution has a number of insoluble particles ≥10 μm of no more than 36 pieces per bottle after a 30-day quality stability test at a temperature of 60°C.

[0028] The technical solution provided by the embodiments of the present application has at least the following advantages compared with the prior art:

[0029] The embodiments of the present application provide a lidocaine hydrochloride injection and a preparation method thereof. Compared with the prior art, the present application mainly adds lidocaine hydrochloride in a suitable weak alkaline environment, which not only improves the dissolution rate and dissolution uniformity of the raw material drug, but also reduces the amplitude of subsequent pH adjustment, greatly reduces the impact on the solution system, enables the entire solution preparation process to be completed at room temperature and more gently, and thus improves the quality stability of the lidocaine hydrochloride injection. DETAILED DESCRIPTION

[0030] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0031] Unless otherwise specified, the various raw materials, reagents, instruments and equipment used in the present application can be purchased from the market or prepared by existing methods. At the same time, the steps and parameters involved in the present application can be performed according to the existing technology disclosed in CN104688675A, CN112933041A and CN115869248A, or directly using existing equipment, if there is no special limitation or specific description. The present application document will not be repeated.

[0032] The present application will be further described in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually determined according to national standards. If there is no corresponding national standard, the general international standard, conventional conditions, or the conditions suggested by the manufacturer are used.

[0033] Example 1

[0034] The present example provides a lidocaine hydrochloride injection. The composition of the lidocaine hydrochloride injection includes: lidocaine hydrochloride 50g; sodium chloride 15g; an appropriate amount of pH adjuster (0.1mol / L sodium hydroxide aqueous solution or 0.1mol / L hydrochloric acid aqueous solution); and water for injection is added to 2.5L, based on 2.5L of the prescribed amount of lidocaine hydrochloride injection.

[0035] The preparation method of the above lidocaine hydrochloride injection includes the following steps:

[0036] (1) Solution preparation

[0037] Add pH regulator to injection water (temperature at room temperature, 25°C) at 78%vol of the prescription amount, adjust pH to 8.5, then add lidocaine hydrochloride at the prescription amount and stir to obtain a first solution;

[0038] Add sodium chloride at the prescription amount to the first solution and stir to obtain a second solution;

[0039] Adjust the pH of the second solution to 5.5 using a pH regulator, then add the remaining injection water (temperature at room temperature, 25°C) to the prescription amount and stir to obtain a lidocaine hydrochloride solution.

[0040] (2) Filtration

[0041] Pass the lidocaine hydrochloride solution through a precision filter containing a 0.45 μm polyether sulfone microporous filter membrane (Hangzhou Kebaiter Filter Material Co., Ltd.) first, then circulate it into the filling process; then pass it through a 0.22 μm polyether sulfone microporous filter membrane filter (Hangzhou Kebaiter Filter Material Co., Ltd., pressure difference before and after filtration not more than 0.2 MPa) sampling port to obtain the filtered lidocaine hydrochloride solution.

[0042] (3) Filling and sealing

[0043] Use transparent glass ampoules, and control the single filling amount to 5.1-5.3 ml.

[0044] (4) Sterilization

[0045] Sterilization temperature 121°C, sterilization time 15 minutes.

[0046] (5) Leak detection, lamp inspection and packaging.

[0047] Example 2

[0048] This example provides a lidocaine hydrochloride injection and a preparation method thereof, which is different from example 1 only in that:

[0049] (1) Solution preparation adjustment:

[0050] Add pH regulator to injection water (temperature at room temperature, 25°C) at 75%vol of the prescription amount, adjust pH to 8.3, then add lidocaine hydrochloride at the prescription amount and stir to obtain a first solution;

[0051] Add sodium chloride at the prescription amount to the first solution and stir to obtain a second solution;

[0052] The pH of the second solution is adjusted to 5.0 using a pH adjuster, and then the remaining water for injection (at room temperature, 25°C) is added to the prescription amount and stirred to obtain a lidocaine hydrochloride solution.

[0053] Example 3

[0054] This example provides a lidocaine hydrochloride injection and a method for preparing the same, which is different from Example 1 only in that:

[0055] (1) The preparation is adjusted as follows:

[0056] A pH adjuster is added to water for injection (at room temperature, 25°C) at 80%vol of the prescription amount, and then the pH is adjusted to 8.8, followed by adding lidocaine hydrochloride of the prescription amount and stirring to obtain a first solution;

[0057] Sodium chloride of the prescription amount is added to the first solution and stirred to obtain a second solution;

[0058] The pH of the second solution is adjusted to 6.0 using a pH adjuster, and then the remaining water for injection (at room temperature, 25°C) is added to the prescription amount and stirred to obtain a lidocaine hydrochloride solution.

[0059] Comparative Example 1

[0060] This example provides a lidocaine hydrochloride injection and a method for preparing the same, which is different from Example 1 only in that:

[0061] (1) The preparation is adjusted as follows:

[0062] A pH adjuster is added to water for injection (at room temperature, 25°C) at 78%vol of the prescription amount, and then the pH is adjusted to 10.0, followed by adding lidocaine hydrochloride of the prescription amount and stirring to obtain a first solution;

[0063] Sodium chloride of the prescription amount is added to the first solution and stirred to obtain a second solution;

[0064] The pH of the second solution is adjusted to 5.5 using a pH adjuster, and then the remaining water for injection is added to the prescription amount and stirred to obtain a lidocaine hydrochloride solution.

[0065] Comparative Example 2

[0066] This example provides a lidocaine hydrochloride injection and a method for preparing the same, which is different from Example 1 only in that:

[0067] (1) The preparation is adjusted as follows:

[0068] A pH adjuster is added to water for injection (at room temperature, 25°C) at 78%vol of the prescription amount, and then the pH is adjusted to 10.0, followed by adding lidocaine hydrochloride of the prescription amount and stirring to obtain a first solution;

[0069] adding a prescribed amount of sodium chloride to the first solution and stirring to obtain a second solution;

[0070] adjusting the pH of the second solution to 5.5 using a pH adjuster, and then adding the remaining water for injection to the prescribed amount and stirring to obtain the lidocaine hydrochloride injection.

[0071] Comparative Example 3

[0072] This example provides a commercially available lidocaine hydrochloride injection, specifically Aspen's Xylocaine®. The specification is 2%.

[0073] Test Example

[0074] This example conducts a 30-day quality stability test on the lidocaine hydrochloride injection obtained in Examples 1-3 and Comparative Examples 1-3 at a temperature of 60°C, and then tests the content of insoluble particles (≥10 μm) in the lidocaine hydrochloride injection sample, and the test results are shown in Table 1.

[0075] Table 1

[0076] Test sample Insoluble particles (> 10 μm), grains / branch Example 1 15 Example 2 36 Example 3 23 Comparative Example 1 801 Comparative Example 2 547 Comparative Example 3 169

[0077] As can be seen from Table 1, compared with Comparative Example 1, Comparative Example 2 and Comparative Example 3, the present application Examples 1-3 achieve the preparation of lidocaine hydrochloride injection at room temperature by using the feeding of lidocaine hydrochloride in a suitable weak alkaline environment, significantly improving the quality stability of the obtained lidocaine hydrochloride injection, so that the number of insoluble particles ≥10 μm in the obtained lidocaine hydrochloride injection after a 30-day quality stability test at a temperature of 60°C is not more than 36 particles per bottle.

[0078] In addition, this example further detects the appearance, content, osmotic pressure and related substance content of the lidocaine hydrochloride injection obtained in Examples 1-3 and Comparative Example 3 according to the Chinese Pharmacopoeia, and the test results show that the other indicators of the lidocaine hydrochloride injection obtained by the present application meet the requirements of the Pharmacopoeia, and the indicators such as the related substance content are slightly better than the existing commercially available product-Comparative Example 3.

[0079] In summary, the present application provides a lidocaine hydrochloride injection and a preparation method thereof, compared with the prior art, the present application mainly feeds the lidocaine hydrochloride in a suitable weak alkaline environment, not only improves the dissolution rate and dissolution uniformity of the raw material drug, but also reduces the amplitude of subsequent pH adjustment, greatly reduces the impact on the solution system, so that the entire solution preparation process can be completed at room temperature and more gently, thereby improving the quality stability of the lidocaine hydrochloride injection.

[0080] Various embodiments of the application can exist in a variety of forms; it should be understood that the description of these embodiments is merely provided for the purposes of clarity and understanding, and is not meant to limit the scope of the application to any one or more of the described embodiments; thus, it should be appreciated that any of the described features can be combined in any combination or sub-combination, and that the description of the scope of the application is intended to cover all such sub-combinations and individual features. For example, it should be appreciated that a range described as from 1 to 6 should be considered to have specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within the described range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. In addition, whenever a numerical range is indicated, it is meant to include any cited number (fraction or integer) within the specified range.

[0081] The above description is meant to be illustrative only and not limiting of the application. Numerous modifications of the embodiments, as described herein, will be apparent to those skilled in the art, and it is intended to use the general principles described herein in other embodiments. Therefore, the present application is not to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing lidocaine hydrochloride injection, characterized in that: The preparation method of the lidocaine hydrochloride injection includes liquid preparation, filtration, filling and sterilization; The solution preparation includes the following process: Adding a pH adjuster to 75-80% of the volume of the prescribed water for injection to adjust the pH to 8.3-8.8, then adding the prescribed amount of lidocaine hydrochloride and stirring to obtain a first solution; adding a prescribed amount of sodium chloride to the first solution and stirring to obtain a second solution; The pH of the second solution is adjusted to 5.0-6.0 using a pH regulator, and then the remaining injection water is added to the prescribed amount and stirred to obtain a lidocaine hydrochloride solution; Wherein, the temperature of the water for injection is room temperature.

2. The method for preparing lidocaine hydrochloride injection according to claim 1, wherein Calculated based on a 2.5L prescription amount of lidocaine hydrochloride injection, the composition of the lidocaine hydrochloride injection includes: Lidocaine hydrochloride 49-51g; Sodium chloride 14-16g; Appropriate amount of pH adjuster; Add water for injection to 2.5L.

3. The method for preparing lidocaine hydrochloride injection according to claim 1, wherein Calculated based on a 2.5L prescription amount of lidocaine hydrochloride injection, the composition of the lidocaine hydrochloride injection includes: Lidocaine hydrochloride 50g; Sodium chloride 15g; Appropriate amount of pH regulator; Add water for injection to 2.5L.

4. The method for preparing lidocaine hydrochloride injection according to claim 1, wherein The pH adjuster includes at least one of a 0.1 mol / L sodium hydroxide aqueous solution and a 0.1 mol / L hydrochloric acid aqueous solution.

5. The method for preparing lidocaine hydrochloride injection according to claim 1, wherein The filtration comprises the following process: filtering the lidocaine hydrochloride solution sequentially through a 0.45 μm polyethersulfone microporous membrane filter and a 0.22 μm polyethersulfone microporous membrane filter.

6. The method for preparing lidocaine hydrochloride injection according to claim 1, wherein The working condition parameters of the filling include: the filling bottle includes at least one of a transparent glass ampoule and a polyethylene ampoule, and the filling volume of a single ampoule is 5.1-5.3 ml.

7. The method for preparing lidocaine hydrochloride injection according to claim 1, characterized in that: The working condition parameters of the sterilization include: temperature of 120-122° C. and time of 15 minutes.

8. The method for preparing lidocaine hydrochloride injection according to any one of claims 1 to 7, characterized in that: The preparation method of the lidocaine hydrochloride injection further comprises leak detection, light inspection and packaging.

9. A lidocaine hydrochloride injection, characterized in that: The lidocaine hydrochloride injection is prepared by the preparation method of lidocaine hydrochloride injection according to any one of claims 1 to 8.

10. The lidocaine hydrochloride injection according to claim 9, characterized in that: After a 30-day quality stability test at 60° C., the number of insoluble particles of 10 μm or larger in the lidocaine hydrochloride injection does not exceed 36 particles per vial.