CN105663035A - Lidocaine hydrochloride injection and preparation method thereof - Google Patents

Abstract

The invention provides a lidocaine hydrochloride injection, which is composed of the following components by weight ratio: per 1000ml: 20g of lidocaine hydrochloride (theoretical amount, the amount of lidocaine hydrochloride needs to be calculated according to the content, moisture content and dryness). Feeding), sodium chloride 4.4 ~ 5.3g. The invention provides an improved lidocaine hydrochloride injection and a preparation method thereof. The formula is simple in composition and involves few types of excipients, which not only eradicates the clinical risk caused by the lack of isotonicity of the product, but also makes the pH of the product, related substances, etc. The indicators are stable and controllable, and all meet the requirements of the 2015 Pharmacopoeia Lidocaine Hydrochloride Injection Draft, which is conducive to clinical use and ensures the safety and effectiveness of the product. The method of the invention is simple, does not increase new costs, is suitable for large-scale industrial production, and has great application value.

Description

A kind of lidocaine hydrochloride injection and preparation method thereof

technical field

The invention relates to a pharmaceutical preparation, in particular to a preparation method of the medicine, in particular to a lidocaine hydrochloride injection and a preparation method thereof.

Background technique

The main component of Lidocaine Hydrochloride Injection is Lidocaine Hydrochloride, which is used in this product as a local anesthetic and an antiarrhythmic drug. It is mainly used for infiltration anesthesia, epidural anesthesia, topical anesthesia (including mucosal anesthesia during thoracoscopic examination or abdominal surgery) and nerve conduction block. This product can also be used for premature ventricular contractions and ventricular tachycardia after acute myocardial infarction, and for ventricular arrhythmias caused by digitalis poisoning, cardiac surgery and cardiac catheterization. But it is usually ineffective for supraventricular arrhythmias.

The indications for lidocaine hydrochloride injection are local anesthetics and antiarrhythmics. It is currently the most commonly used local anesthetic in clinical practice. mucosal anesthesia) and nerve conduction blockade. This product can also be used for premature ventricular contractions and ventricular tachycardia after acute myocardial infarction, and for ventricular arrhythmias caused by digitalis poisoning, cardiac surgery and cardiac catheterization. However, since lidocaine hydrochloride injection is often used clinically for epidural block and caudal block, this route of administration has a high risk to the human body. If the drug solution is not isotonic, it will increase the risk of clinical medication , Serious cases may even lead to irreversible damage or even death of the patient. However, the current version of the Chinese Pharmacopoeia standard for lidocaine hydrochloride injection does not require the osmotic pressure of the drug, and the risk caused by the non-isotonicity of the product cannot be avoided. At the same time, the pH standard of lidocaine hydrochloride injection in the current version of the Chinese Pharmacopoeia is pH 3.5 to 5.5, but lower pH values often cause irritation in patients taking the drug, and lidocaine hydrochloride injections at lower pH values The anesthesia effect of Caine Hydrochloride Injection is not obvious, so before clinical use, medical personnel often adjust the pH of Lidocaine Hydrochloride Injection to 5.0-7.0 (clinical studies have shown that the anesthetic effect of Lidocaine Hydrochloride Injection increases with the increase of pH). Enhanced, the best at pH 5.0-7.0). There are also literatures that show that when the pH is greater than 6.0, the stability of the solution is relatively poor, and particles are precipitated, so it is necessary to prepare it immediately before use. However, due to the lack of necessary detection methods and the influence of the quality of personnel, this process may greatly increase the clinical The risks of drug use.

Based on the safety and effectiveness of clinical medication of lidocaine hydrochloride injection, the quality standard of lidocaine hydrochloride injection was revised in the 2015 edition of the Chinese Pharmacopoeia for comments, mainly reflected in the osmolality and pH value indicators, The pH value was adjusted to pH 4.0-6.0, and the osmolarity standard was set at 285-310 mOsm/Kg.

Existing lidocaine hydrochloride injection formulation process:

serial number Element 1000ml theoretical formula quantity 1 Lidocaine Hydrochloride 20g 2 Sodium chloride 8.5g 3 purified water Add to 1000ml

Remarks: The main drug dosage of lidocaine hydrochloride needs to be fed according to the content and moisture content.

1. Preparation: Weigh sodium chloride, lidocaine hydrochloride, and medicinal charcoal according to the formula, and set aside.

2. Washing and drying bottles: Use an ultrasonic washing machine to clean the ampoule.

3. Dosing:

3.1. Put 70% of the water for injection in the formula into the liquid mixing tank, add the sodium chloride in the formula, turn on the mixer and stir for 5 minutes.

3.2. Add the prescribed amount of lidocaine hydrochloride into the liquid mixing tank and stir for 5 minutes.

3.3. Add the formula amount of medicinal charcoal and stir for 5 minutes.

3.4. Add water for injection, turn on the mixer and stir for 5 minutes.

3.5. The solution was circulated and filtered with a titanium filter for 10 minutes.

3.6. The solution is circulated and filtered with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 15 minutes.

3.7. Adjust the pH value to 4.0-5.0.

4. Potting and sealing: adjust the filling volume, and carry out filling and sealing under the A-level laminar flow hood.

5. Sterilization: Sterilize at 116°C for 30 minutes.

6. Light inspection: use artificial light inspection or automatic light inspection machine for light inspection.

7. Printing, packaging and storage.

However, under the existing formula and process conditions of lidocaine hydrochloride injection, its osmotic pressure is about 415mOsm/Kg, which is far greater than the isotonic requirement of 285mOsm/Kg-310mOsm/Kg.

Contents of the invention

The technical problem to be solved by the present invention is to overcome above-mentioned deficiencies, research and design osmolarity and pH are all in the controllable process quality stable, safer and more effective clinical prescription and preparation of lidocaine hydrochloride injection method.

The invention provides a lidocaine hydrochloride injection.

Described injection is made up of the composition (every 1000ml) of following weight ratio:

serial number Element 1000ml theoretical formula quantity 1 Lidocaine Hydrochloride 20g 2 Sodium chloride 4.4-5.3g 3 purified water Add to 1000ml

Remarks: The main drug dosage of lidocaine hydrochloride needs to be fed according to the content and moisture content.

Another object of the present invention provides the preparation method of above-mentioned lidocaine hydrochloride injection, and this method comprises the following steps:

(1), preparation: take by weighing sodium chloride, lidocaine hydrochloride, medicinal charcoal, standby;

(2), washing and drying bottles: use an ultrasonic washing machine to clean the ampoule;

(3), dosing:

(3.1), put the water for injection of 70% formula quantity into the liquid mixing tank, add sodium chloride, turn on the mixer and stir for 5 minutes;

(3.2), add lidocaine hydrochloride in the liquid mixing tank, stir for 5 minutes;

(3.3), add medicinal charcoal, stir for 5 minutes;

(3.4), add water for injection, turn on the mixer and stir for 5 minutes;

(3.5), the solution was circulated and filtered with a titanium filter for 10 minutes;

(3.6), the solution is circulated and filtered for 15 minutes with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter;

(3.7), adjust the pH value to 4.0～6.0; adjust the osmotic pressure to be 292mOsm/Kg～310mOsm/Kg;

(4), potting: adjust the filling capacity, and potting is carried out under the A-level laminar flow hood;

(5) Sterilization: Sterilize at 116°C for 30 minutes;

(6) Light inspection: use manual light inspection or automatic light inspection machine for light inspection;

(7) Printing, packaging, and storage.

Step (3.7) of the present invention adjusts the pH value to 4.0-6.0; preferably adjusts the pH value to 5.0-5.5; selects sodium hydroxide, potassium hydroxide or sodium acetate, potassium acetate to adjust the pH value.

Step (3.7) of the present invention adjusts the osmotic pressure to 285mOsm/Kg-310mOsm/Kg; preferably adjusts the osmotic pressure to 292mOsm/Kg-310mOsm/Kg.

The invention provides an improved lidocaine hydrochloride injection and a preparation method thereof, which not only eradicates the clinical risk caused by the lack of isotonicity of the product, but also makes the pH of the product more favorable for clinical use, avoiding the need for medical personnel to adjust the pH before clinical use, It reduces the clinical adverse reactions caused by improper operation of medical personnel and ensures the safety and effectiveness of the product. The method of the invention is simple, does not increase new costs, is suitable for large-scale industrial production, and has great application value.

detailed description

The raw materials used in the following examples are commercially available.

Example 1 prepares lidocaine hydrochloride injection:

serial number Element 1000ml recipe volume 1 Lidocaine Hydrochloride 21.565g 2 Sodium chloride 4.9g 3 purified water Add to 1000ml

(1), preparation: take by weighing sodium chloride, lidocaine hydrochloride, medicinal charcoal according to formula quantity, for subsequent use.

(2) Washing and drying the bottle: use an ultrasonic washing machine to clean the ampoule.

(3), dosing:

(3.1), put the water for injection of 70% formula quantity into the liquid mixing tank, add the sodium chloride of formula quantity, turn on the mixer and stir for 5 minutes.

(3.2), add the lidocaine hydrochloride of formula quantity in the liquid mixing tank, stir for 5 minutes.

(3.3), add medicinal charcoal according to the formula, and stir for 5 minutes.

(3.4), add water for injection, turn on the mixer and stir for 5 minutes.

(3.5), the solution was circulated and filtered with a titanium filter for 10 minutes.

(3.6), the solution is circulated and filtered for 15 minutes with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter.

(3.7), use sodium hydroxide aqueous solution (10%) to adjust the pH value to 5.0～5.5; adjust the osmotic pressure to be 292mOsm/Kg～310mOsm/Kg. Sampling is taken to determine the content of the intermediate, and the content is controlled at 97.0-103.0% of the marked amount.

(4), potting: adjust the filling volume, and potting is carried out under the A-level laminar flow hood.

(5) Sterilization: Sterilize at 116° C. for 30 minutes.

(6) Light inspection: Use artificial light inspection to perform light inspection.

(7) Printing, packaging, and storage.

Example 2 prepares lidocaine hydrochloride injection:

serial number Element 1000ml recipe volume 1 Lidocaine Hydrochloride 21.565g 2 Sodium chloride 4.4g 3 purified water Add to 1000ml

Remarks: lidocaine hydrochloride is fed according to the content and water content of the dry product.

(1), preparation: take by weighing sodium chloride, lidocaine hydrochloride, medicinal charcoal according to formula quantity, for subsequent use.

(2) Washing and drying the bottle: use an ultrasonic washing machine to clean the ampoule.

(3), dosing:

(3.1), put the water for injection of 70% formula quantity into the liquid mixing tank, add the sodium chloride of formula quantity, turn on the mixer and stir for 5 minutes.

(3.2), add the lidocaine hydrochloride of formula quantity in the liquid mixing tank, stir for 5 minutes.

(3.3), add medicinal charcoal according to the formula, and stir for 5 minutes.

(3.4), add water for injection, turn on the mixer and stir for 5 minutes.

(3.5), the solution was circulated and filtered with a titanium filter for 10 minutes.

(3.6), the solution is circulated and filtered for 15 minutes with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter.

(3.7), use sodium hydroxide aqueous solution (15%) to adjust the pH value to 4.0～4.5; adjust the osmotic pressure to be 280mOsm/Kg～290mOsm/Kg. Sampling is taken to determine the content of the intermediate, and the content is controlled at 97.0-103.0% of the marked amount.

(4), potting: adjust the filling volume, and potting is carried out under the A-level laminar flow hood.

(5) Sterilization: Sterilize at 116° C. for 30 minutes.

(6) Light inspection: automatic light inspection machine for light inspection.

(7) Printing, packaging, and storage.

Example 3 prepares lidocaine hydrochloride injection:

serial number Element 1000ml recipe volume 1 Lidocaine Hydrochloride 21.565g 2 Sodium chloride 5.3g 3 purified water Add to 1000ml

Remarks: Lidoca hydrochloride is divided into dry and pure according to the content and water content.

(1), preparation: take by weighing sodium chloride, lidocaine hydrochloride, medicinal charcoal according to formula quantity, for subsequent use.

(2) Washing and drying the bottle: use an ultrasonic washing machine to clean the ampoule.

(3), dosing:

(3.1), put the water for injection of 70% formula quantity into the liquid mixing tank, add the sodium chloride of formula quantity, turn on the mixer and stir for 5 minutes.

(3.2), add the lidocaine hydrochloride of formula quantity in the liquid mixing tank, stir for 5 minutes.

(3.3), add medicinal charcoal according to the formula, and stir for 5 minutes.

(3.4), add water for injection, turn on the mixer and stir for 5 minutes.

(3.5), the solution was circulated and filtered with a titanium filter for 10 minutes.

(3.6), the solution is circulated and filtered for 15 minutes with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter.

(3.7), use potassium hydroxide aqueous solution (10%) to adjust the pH value to 5.5～6.0; adjust the osmotic pressure to be 292mOsm/Kg～310mOsm/Kg.

Sampling is taken to determine the content of the intermediate, and the content is controlled at 97.0-103.0% of the marked amount.

(4), potting: adjust the filling volume, and potting is carried out under the A-level laminar flow hood.

(5) Sterilization: Sterilize at 116° C. for 30 minutes.

(6) Light inspection: Use an automatic light inspection machine for light inspection.

(7) Printing, packaging, and storage.

The lidocaine hydrochloride injection that embodiment 1-3 produces is carried out every index investigation, and result is as follows:

The results show that all indicators of the lidocaine hydrochloride injection produced in Examples 1-3 meet the standard requirements, pH and osmotic pressure meet the requirements for clinical use, the production process is controllable, and it meets the requirements for large-scale continuous and stable production.

Comparative example: the following are products produced by the existing preparation process,

Existing lidocaine hydrochloride injection formulation process:

serial number Element 1000ml theoretical formula quantity 1 Lidocaine Hydrochloride 20g 2 Sodium chloride 8.5g 3 purified water Add to 1000ml

Remarks: The main drug dosage of lidocaine hydrochloride needs to be fed according to the content and moisture content.

1. Preparation: Weigh sodium chloride, lidocaine hydrochloride, and medicinal charcoal according to the formula, and set aside.

2. Washing and drying bottles: Use an ultrasonic washing machine to clean the ampoule.

3. Dosing:

3.1. Put 70% of the water for injection in the formula into the liquid mixing tank, add the sodium chloride in the formula, turn on the mixer and stir for 5 minutes.

3.2. Add the prescribed amount of lidocaine hydrochloride into the liquid mixing tank and stir for 5 minutes.

3.3. Add the formula amount of medicinal charcoal and stir for 5 minutes.

3.4. Add water for injection, turn on the mixer and stir for 5 minutes.

3.5. The solution was circulated and filtered with a titanium filter for 10 minutes.

3.6. The solution is circulated and filtered with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter for 15 minutes.

3.7. Adjust the pH value to 4.0-5.0.

4. Potting and sealing: adjust the filling volume, and carry out filling and sealing under the A-level laminar flow hood.

5. Sterilization: Sterilize at 116°C for 30 minutes.

6. Light inspection: use artificial light inspection or automatic light inspection machine for light inspection.

7. Printing, packaging and storage.

The inspection results of various indicators of the three batches of samples are as follows:

It can be seen from the above table that the pH of the three samples is low, and the osmotic pressure far exceeds the requirement of isotonicity. The products cannot meet the requirements of clinical use, and the safety of clinical medication cannot be guaranteed.

Example 4 prepares lidocaine hydrochloride injection

Composition and preparation are with example 1

Example 5 prepares lidocaine hydrochloride injection

Composition and preparation are the same as example 2

Example 6 prepares lidocaine hydrochloride injection

Composition and preparation are with example 3

The lidocaine hydrochloride injection that above-mentioned embodiment 4-6 prepares all meets lidocaine hydrochloride injection (Chinese Pharmacopoeia 2015 edition two third drafts for comments) (see below)

Lidocaine hydrochloride injection quality standard

Chinese Pharmacopoeia 2015 Edition Part Two Discussion Draft

This product is a sterilized aqueous solution of lidocaine hydrochloride, containing lidocaine hydrochloride (C14H22N2O·HCl) should be 95.0% to 105.0% of the labeled amount.

【Properties】This product is a colorless clear liquid.

[Identification] (1) Take this product, according to the identification (1) and (3) tests under lidocaine hydrochloride item, the same result is shown.

(2) In the chromatogram recorded under the assay item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference substance solution.

【Check】The pH value should be 4.0～6.0 (Appendix VIH).

[Related substances] Accurately measure an appropriate amount of this product, quantitatively dilute it into a solution containing 2mg of lidocaine hydrochloride in every 1ml with mobile phase, as the solution for the test; accurately measure 1ml, place it in a 100ml measuring bottle, and Phase diluted to the mark, as the reference solution; take another 2,6-dimethylaniline reference substance, accurately weighed, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 0.8 μg per 1ml, as the reference substance solution. According to the chromatographic conditions under the content determination item, the detection wavelength is 230nm, and 20 μl of contrast solution is taken, injected into a liquid chromatograph, and the detection sensitivity is adjusted so that the peak height of the main component chromatographic peak is about 20% of the full scale; Each 20 μl of the three solutions is injected into the liquid chromatograph respectively, and the chromatogram is recorded to 3.5 times of the retention time of the main component peak. If there is a chromatogram with the same retention time as 2,6-dimethylaniline Peak, its peak area must not be greater than the reference substance solution main peak area (0.04%), other single impurity peak area must not be greater than 0.5 times (0.5%) the contrast solution main peak area, the sum of other each impurity peak area must not be greater than the contrast solution main peak area (1.0 %).

Bacterial endotoxins Take this product and check according to the law (Appendix XIE). The amount of endotoxin contained in every 1mg of lidocaine hydrochloride should be less than 0.040EU.

Osmolality Take this product, check according to the law (Appendix IXG), the osmolality should be 285～310mOsm0l/Kg.

Others should comply with the relevant regulations under injection (Appendix IB)

【Content Determination】Determination according to high performance liquid chromatography (Appendix VD).

Chromatographic conditions and system suitability test use octadecylsilane bonded silica gel as filler; use phosphate buffer (take 1.3ml of 1mol/L sodium dihydrogen phosphate solution and 32.5ml of 0.5mol/L disodium hydrogen phosphate solution, Put it in a 1000ml measuring bottle, add water to dilute to the mark, shake well)-acetonitrile (50:50) and adjust the pH value to 8.0 with phosphoric acid as the mobile phase; the detection wavelength is 254nm. The theoretical plate number should not be less than 2000 based on the lidocaine peak.

Determination method Accurately measure an appropriate amount of this product (approximately equivalent to 100 mg of lidocaine hydrochloride), put it in a 50ml measuring bottle, dilute to the mark with mobile phase, shake well, accurately measure 20 μl and inject it into a liquid chromatograph, and record the chromatogram; Take about 85mg of lidocaine reference substance, weigh it accurately, put it in a 50ml measuring bottle, add 0.5ml of 1mol/L hydrochloric acid solution to dissolve, dilute to the mark with mobile phase, shake well, and measure in the same way. According to the external standard method to calculate the peak area, and multiplied by 1.156, that is.

【Category】Same as lidocaine hydrochloride.

[Specification] (1) 2ml: 20mg (2) 2ml: 40mg (3) 3.5ml: 35mg (4) 5ml: 50mg (5) 5ml: 0.1g (6) 10ml: 0.2g (7) 20ml: 0.4g

【Storage】Keep airtight.

The data full inspection result of the lidocaine hydrochloride injection finished product that above-mentioned example 4-6 prepares.

Claims (7)

1. a lidocaine hydrochloride injection, is characterized in that, described injection is made up of the composition of following weight ratio: per 1000ml Lidocaine hydrochloride 20g Sodium chloride 4.4～5.3g Add purified water to 1000ml; The amount of lidocaine hydrochloride is calculated according to content and water content in dry form and pure feed intake. 2. a lidocaine hydrochloride injection, is characterized in that, described lidocaine hydrochloride injection is made up of the composition of following weight ratio: per 1000ml Lidocaine hydrochloride 20g Sodium chloride 4.9g Add purified water to 1000ml; The amount of lidocaine hydrochloride is calculated according to content and water content in dry form and pure feed intake. 3. prepare the method for a kind of lidocaine hydrochloride injection as claimed in claim 1 or 2, it is characterized in that, the method may further comprise the steps: (1), preparation: take by weighing sodium chloride, lidocaine hydrochloride, medicinal charcoal, standby; (2), washing and drying bottles: use an ultrasonic washing machine to clean the ampoule; (3), dosing: (3.1), put the water for injection of 70% formula quantity into the liquid mixing tank, add sodium chloride, turn on the mixer and stir for 5 minutes; (3.2), add lidocaine hydrochloride in the liquid mixing tank, stir for 5 minutes; (3.3), add medicinal charcoal, stir for 5 minutes; (3.4), add water for injection, turn on the mixer and stir for 5 minutes; (3.5), the solution was circulated and filtered with a titanium filter for 10 minutes; (3.6), the solution is circulated and filtered for 15 minutes with a titanium filter, a 0.45 μm microporous membrane cartridge filter and a 0.2 μm microporous membrane cartridge filter; (3.7), adjust the pH value to 4.0～6.0; adjust the osmotic pressure to be 292mOsm/Kg～310mOsm/Kg; (4), potting: adjust the filling capacity, and potting is carried out under the A-level laminar flow hood; (5) Sterilization: Sterilize at 116°C for 30 minutes; (6) Light inspection: use manual light inspection or automatic light inspection machine for light inspection; (7) Printing, packaging, and storage. 4. The method according to claim 3, characterized in that in step 3.7, the pH value is adjusted to 4.0-6.0, and the pH regulator is selected from sodium hydroxide or potassium hydroxide. 5. The method according to claim 4, characterized in that in step 3.7, the pH value is adjusted to 5.0-5.5. 6. The method according to claim 3, characterized in that, the osmolarity in the step 3.7 is 285mOsm/Kg-310mOsm/Kg. 7. The method according to claim 6, characterized in that the osmolarity in step 3.7 is 292 mOsm/Kg-310 mOsm/Kg.