Compound articaine hydrochloride injection and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, relates to an oral local anesthetic, and is particularly suitable for the surgical operation process related to osteotomy and mucous membrane incision. In particular to a compound articaine hydrochloride injection and a preparation method thereof. The compound articaine hydrochloride injection is a ready-to-use liquid injection. The preparation provided by the invention is reasonable in prescription design, and is mainly prepared from main drugs, namely articaine hydrochloride, pituitary posterior leaf element and tranexamic acid, and auxiliary materials, namely an antioxidant, an osmotic pressure regulator and a pH (Potential of Hydrogen) regulator. The invention also provides a preparation method of the composition. The articaine injection product prepared by adopting the raw materials and the auxiliary materials and the preparation method provided by the invention prolongs the anesthesia time, reduces bleeding of an operation site, is good in stability, can be placed at normal temperature for more than 6 months, retains the effective content by more than 98%, and is suitable for clinical use.

Description

Technical Field

[0001] The present invention belongs to the field of anesthetic preparation, and particularly relates to a compound articaine hydrochloride injection for injection and a preparation method thereof. Background Art

[0002] During the current surgical treatment of oral pulp diseases, procaine and lidocaine injections are generally used for anesthesia during the operation. However, their anesthetic mechanism only plays an anesthetic role through nerve block. The efficacy evaluation shows that although the anesthesia is effective, patients will feel pain during the operation and need to endure it to complete the surgical operation.

[0003] Compound articaine hydrochloride injection, a new type of amide oral anesthetic, was developed by SEPTODONT Company in France. It is a local anesthetic used in the surgical treatment of oral pulp diseases in recent years. The common specification is 1.7 ml: 68 mg of articaine hydrochloride and 17 μg of adrenaline. The main components are 4% of articaine hydrochloride and 1:100,000 of adrenaline, which is a small-volume injection. Its mechanism of action is that the main component, articaine, acts on the sodium ion channels on the nerve cell membrane to prevent the influx of sodium ions, thereby blocking the conduction of nerve impulses and producing anesthetic effects.

[0004] The main component of compound articaine hydrochloride injection is articaine hydrochloride, with the chemical name of methyl 4-methyl-3-[[1-oxo-2-(propylamino)propyl]amino]-2-thiophenecarboxylate hydrochloride. It is a white to off-white crystalline powder. It is readily soluble in water and ethanol.

[0005] Chemical structural formula: Molecular formula: C 13 H 20 N2O3S·HCl Molecular weight: 320.84 At present, the articaine adrenaline injection used in clinical practice still has some deficiencies. The adrenaline in its prescription has problems such as poor stability, obvious side effects (such as cardiovascular stimulation), or intolerance in some patients. Although adrenaline can prolong the anesthetic time, the drug efficacy duration is still insufficient in some cases, and the drug stability still needs to be improved. Summary of the Invention

[0006] In view of the limitations of the current articaine injection and other problems, the purpose of the present invention is to provide a compound articaine hydrochloride injection.

[0007] Another object of the present invention is to provide a preparation method of the above compound articaine hydrochloride injection.

[0008] The technical solution adopted by the present invention to achieve the above object is as follows: The present invention provides a compound articaine hydrochloride injection, which is composed of the following components: 1.36 kg of articaine hydrochloride, 391 mg of pituitrin, 100 g of hemostatic agent, 16.15 g - 17.85 g of sodium metabisulfite, 32.3 g - 35.7 g of sodium chloride, a pH regulator, and the injection water is added to 34000 ml.

[0009] Preferably, the hemostatic agent is one or more of etamsylate, tranexamic acid, aminocaproic acid, carbazochrome sodium sulfonate, aminomethylbenzoic acid, and carbazochrome.

[0010] Preferably, the hemostatic agent is tranexamic acid.

[0011] Preferably, the pH regulator includes one or more of 10% hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; preferably, the pH regulator is 10% hydrochloric acid or sodium hydroxide.

[0012] The present invention also provides a preparation method of the above compound articaine hydrochloride injection, which is characterized by including the following steps: ①Cool 70% - 80% of the total amount of injection water to 25°C or below, and fill with a nitrogen-carbon dioxide mixed gas; ②Add sodium metabisulfite and sodium chloride to the injection water filled with the mixed gas, stir and dissolve; then add articaine hydrochloride, the hemostatic agent, and pituitrin, stir and dissolve, and adjust the pH value; ③Add injection water to 34000 ml, stir evenly, and sterilize; ④Pre-fill and seal syringes or ampoules for packaging.

[0013] Preferably, in step ②, the mixed gas is composed of nitrogen and carbon dioxide in a volume ratio of 100:1; adjust the pH value to 3.0 - 5.0.

[0014] Preferably, during the preparation process, the temperature of the overall system is kept below 25°C.

[0015] For the compound articaine hydrochloride injection described in the present invention, the amount of articaine hydrochloride is the amount after purification.

[0016] Since the raw material of pituitrin is thermally unstable, the temperature of water or solution should be kept below 25°C during the preparation process; to prevent the loss of pituitrin during the preparation process, generally 10 - 15% more feeding amount will be added.

[0017] After the injection is prepared and before filling, samples are taken for intermediate product inspection; the inspection standards are as follows: Appearance: This product is a colorless to slightly yellowish clear liquid; pH value: 3.0 - 5.0 Articaine Hydrochloride: 99.0% - 101.0% During the filling and sealing process, nitrogen gas is used to blow the bottles; the ampoules or pre-filled syringes used are brown bottles; After filling, it also includes lamp inspection to check for visible foreign matters, filling volume, and color and luster.

[0018] Moreover, to ensure the stability of the system, steps (1) - (5) should all be protected by a protective gas; generally, it can be achieved by continuously filling the solution with a protective gas or conducting the process under an inert gas.

[0019] The protective gas described in the present invention refers to commonly used industrially chemically inert protective gases such as nitrogen, hydrogen, and helium; since nitrogen is not only chemically very inert but also can remove the residual oxygen in the liquid and protect the stability of some substances that are unstable in the presence of oxygen and prone to oxidation, nitrogen is preferred. Specific Embodiments

[0020] The technical solutions of the present invention will be further explained and illustrated below through specific examples. The following examples are used to illustrate the present invention but not to limit the scope of the present invention.

[0021] Example 1 1. Prescription Articaine Hydrochloride 400g Pituitrin 115mg Etamsylate 29.4g Sodium Pyrosulfite 5.0g Sodium Chloride 10g 10% Hydrochloric Acid q.s. Sodium Hydroxide q.s. Water for Injection up to 10000ml 2. Preparation Process Add 8000ml of water for injection (about 80% of the total amount) to the preparation container, cool the temperature to below 25°C, and set aside; continuously fill the water for injection with a mixed gas of nitrogen - carbon dioxide (volume ratio 100:1); sequentially add the prescribed amounts of sodium pyrosulfite and sodium chloride and stir to dissolve; add articaine hydrochloride and stir to dissolve; add etamsylate and stir to dissolve; add pituitrin and stir to dissolve; use 10% hydrochloric acid and sodium hydroxide to adjust the pH value; add water for injection to 10000ml and stir evenly; filter and sterilize through a 0.22um microporous filter element; fill and seal, and package.

[0022] Sampling and Inspection: pH value: 4.0 Content of Articaine Hydrochloride: 99% Content of Pituitrin: 100.3% Content of Etamsylate: 98.6% The above content is based on the formulated amount being 100%. Obviously, through the improvement of the product prescription and process conditions and the adjustment of process parameters during the operation process, and by conducting a full - item inspection of the product according to the established standards, the results show that all detection indicators meet the standard requirements. Thus, it can be confirmed that this prescription and operation process are feasible.

[0023] Example 2 1. Prescription Articaine Hydrochloride 400g Pituitrin 115mg Tranexamic Acid 29.4g Sodium Pyrosulfite 5.0g Sodium Chloride 10g 10% Hydrochloric Acid q.s. Sodium Hydroxide q.s. Water for Injection up to 10000ml 2. Preparation Process Add 8000ml of water for injection (about 80% of the total amount) to the preparation container, cool the temperature to below 25°C, and set aside. Continuously charge a nitrogen - carbon dioxide mixed gas (volume ratio 100:1) into the water for injection. Add the prescribed amounts of sodium pyrosulfite and sodium chloride in sequence and stir to dissolve. Add articaine hydrochloride and stir to dissolve. Add tranexamic acid and stir to dissolve. Add pituitrin and stir to dissolve. Use 10% hydrochloric acid and sodium hydroxide to adjust the pH value. Add water for injection to 10000ml and stir evenly. Filter and sterilize through a 0.22μm microporous filter element. Fill and seal, and package.

[0024] Sampling and Inspection: pH value: 4.3 Content of Articaine Hydrochloride: 99% Content of Pituitrin: 101% Content of Tranexamic Acid: 101% The above content is based on the formulated amount being 100%.

[0025] Obviously, through the improvement of the product prescription and process conditions and the adjustment of process parameters during the operation process, and by conducting a full - item inspection of the product according to the established standards, the results show that all detection indicators meet the standard requirements. Thus, it can be confirmed that this prescription and operation process are feasible. The specific results are shown in Table 1.

[0026] Comparative Example 1 1. Prescription Articaine Hydrochloride 400g Adrenaline 115mg Sodium Pyrosulfite 5.0g Sodium Chloride 16g 10% Hydrochloric Acid Q.S. Sodium Hydroxide Q.S. Water for Injection q.s. to 10000 ml 2. Preparation Process Add ~80% of the total amount of water for injection to the preparation container, cool the temperature to below 25°C, and set aside; continuously charge nitrogen into the water for injection; successively add the prescribed amounts of sodium metabisulfite and sodium chloride and stir to dissolve; add articaine hydrochloride and stir to dissolve; weigh 0.23 g of adrenaline, dissolve it with 10% hydrochloric acid solution, and the dosage is 4.2 ml; use 10% hydrochloric acid and sodium hydroxide to adjust the pH value; add it to a 1000 ml volumetric flask, dilute it to the mark with water, accurately measure 500 ml of adrenaline solution and add it to the above solution, about 115 mg of adrenaline (15% overdosage of adrenaline); add water for injection to 10000 ml, stir evenly; filter through a 0.22 μm microporous filter element; fill and seal, sterilize, and package.

[0027] Sampling and Inspection: pH value: 4.0 Content of articaine hydrochloride: 99% Content of adrenaline: 100.1% The above contents are based on 100% of the formulated amount.

[0028] Comparative Example 2 1. The prescription is the same as that in Example 3; 2. Preparation Process Add 8000 ml of water for injection (about 80% of the total amount) to the preparation container, cool the temperature to below 25°C, and set aside; continuously charge nitrogen into the water for injection; successively add the prescribed amounts of sodium metabisulfite and sodium chloride and stir to dissolve; add articaine hydrochloride and stir to dissolve; add tranexamic acid and stir to dissolve; add pituitrin and stir to dissolve; use 10% hydrochloric acid and sodium hydroxide to adjust the pH value; add water for injection to 10000 ml, stir evenly; filter and sterilize through a 0.22 μm microporous filter element; fill and seal, and package.

[0029] Effect Example 1 Stability Test Stability Test: Produce three batches of samples according to the production process determined in Example 2, conduct stability investigation according to the conditions of accelerated stability test and long-term stability test, and statistically analyze the detected data. The results are shown in Table 1.

[0030] Table 1 Stability of Compound Articaine Hydrochloride Injection (Specification: 1.7 ml) Conclusion: According to the requirements of the product's prescription, production process conditions, and key quality control points, statistical analysis was conducted on the production process of the continuously produced products and the observed data of the retained samples. The quality conditions such as the content of each substance and pH value of the product have been relatively stable and all meet the quality standard requirements. It is worth noting that in Comparative Example 2, when only single nitrogen gas was used, under the same detection conditions, the impurity content increased to 0.49% in the 12th month of the long-term test; and the impurity content increased to 0.68% in the 12th month of the accelerated test.

[0031] Effect Example 2 Application Effect Test (1) Verify the anesthetic duration, hemostatic effect, and systemic absorption of the new prescription.

[0032] 1. Anesthetic Duration Test Design 1.1 Animal model: Healthy adult rabbits (2.5 - 3.0 kg) were used as experimental subjects. Grouping: The rabbits were randomly divided into 4 groups, with 10 rabbits in each group: Group A (Control Group 1 - Comparative Example 1): Use the existing articaine adrenaline injection; Group B (Example 1): Articaine + pituitrin + etamsylate; Group C (Example 2): Articaine + pituitrin + tranexamic acid; Group D ((Control Group 2 - Comparative Example 2)).

[0033] 1.2 Test steps 1. Inject the solution beside the apex of the second maxillary molar of the rabbit (standard injection position).

[0034] 2. Record the anesthetic onset time after injection (test the rabbit's reaction to pain with a needle prick).

[0035] 3. Test the rabbit's pain reaction at regular intervals (every 10 minutes) until complete recovery, and record the anesthetic duration.

[0036] 1.3 Evaluation indicators Onset time: The time from injection to the disappearance of the pain reaction.

[0037] Duration: The time from onset to complete recovery of the pain reaction.

[0038] 2. Hemostatic Effect Test Design 1.1 Animal model: Healthy adult rats (250 - 300 g) were used. Grouping: The same as the anesthetic duration test.

[0039] 1.2 Test steps 1. Make a 5 - mm standard wound on the rat's tail after anesthesia, controlling the incision depth (about 1 mm).

[0040] 2. Immediately inject the corresponding test solution locally around the wound.

[0041] 3. Collect the blood flowing out of the wound and weigh it every 30 seconds until bleeding stops completely.

[0042] 1.3 Evaluation indicators Hemostasis time: The time from injecting the test solution to complete hemostasis.

[0043] Blood loss: The total amount of blood lost before complete hemostasis.

[0044] 3. Systemic absorption test design 1.1 Animal model: Healthy adult dogs (10 - 12 kg). Grouping: The same as the first two parts of the experiment.

[0045] 1.2 Test procedures 1. Inject the test solution into the subcutaneous tissue on the outer side of the dog's front leg.

[0046] 2. Collect blood samples at specific time points (0, 5, 15, 30, 60, 120, 240 minutes).

[0047] 3. Use high - performance liquid chromatography (HPLC) method to detect the blood drug concentrations of articaine hydrochloride and vasoconstrictor (pituitrin).

[0048] 1.3 Evaluation indicators Pharmacokinetic parameters: including C max (maximum blood drug concentration), T max (time to peak concentration), AUC (area under the curve), t 1 / 2 (half - life).

[0049] Systemic side effects: Observe whether the dogs have adverse reactions such as abnormal heart rate and blood pressure changes.

[0050] (2) Application effect test data and analysis 1. Anesthesia duration test data Table 2 2. Hemostasis effect test data table Table 3 3. Systemic absorption test data table Table 4 Conclusion: 1. Anesthesia duration: It is expected that the anesthesia duration of the new prescriptions (Group B and Group C) is slightly longer than that of Group A. 2. Hemostasis effect: The new prescriptions are superior to Group A in terms of hemostasis time and blood loss, especially Group C (tranexamic acid). 3. Systemic absorption: The peak blood drug concentration and systemic absorption rate of the new prescriptions are lower than those of Group A, with fewer side effects and improved safety.

[0051] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent replacements or changes should be covered within the protection scope of the present invention.

Claims

1. A compound articaine hydrochloride injection, characterized in that: The composition is composed of the following components: 1.36 kg of articaine hydrochloride, 340 mg of posterior pituitary hormone, 100 g of hemostatic agent, 17 g of sodium pyrosulfite, 34 g of sodium chloride, a pH regulator, and water for injection is added to 34000 ml.

2. The compound articaine hydrochloride injection according to claim 1, characterized in that: The hemostatic agent is one or more of ethamine, tranexamic acid, aminocaproic acid, carbazochrome sodium sulfonate, aminobenzoic acid and carbachol.

3. The compound articaine hydrochloride injection according to claim 2, characterized in that: The hemostatic agent is tranexamic acid.

4. The compound articaine hydrochloride injection according to claim 1, characterized in that: The pH regulator is one or more of 10% hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

5. The compound articaine hydrochloride injection according to claim 4, characterized in that: The pH regulator is 10% hydrochloric acid or sodium hydroxide.

6. A method for preparing the compound articaine hydrochloride injection as described in any one of claims 1 to 5, characterized in that: The following steps are involved: ① Cool the water for injection, which accounts for 70% to 80% of the total volume, to 25°C or below and fill it with nitrogen; ② Add sodium metabisulfite and sodium chloride to the injection water filled with mixed gas, stir and dissolve; then add articaine hydrochloride, hemostatic agent and posterior pituitary hormone, stir and dissolve; adjust the pH value; ③ Add water for injection to 34000ml, stir evenly and sterilize; ④ Filling and packaging of prefilled syringes or ampoules.

7. The preparation method according to claim 6, characterized in that: In step ②, the mixed gas is nitrogen and carbon dioxide, and the volume ratio of nitrogen to carbon dioxide is 100:1; the pH value is adjusted to 3.0-5.

0.

8. The preparation method according to claim 6 or 7, characterized in that: During the preparation process, the temperature of the entire system was maintained below 25°C.

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