A dimethocaine compound preparation and preparation method thereof

Abstract

The present invention provides a dimethicaine compound formulation and a preparation method thereof. The dimethicaine compound formulation comprises the following raw materials in parts by weight per 100 parts of the compound formulation: 2-5 parts of dimethicaine and 2-5 parts of trimecaine. The dimethicaine compound formulation contains chlorhexidine gluconate, Tween 80, oleic acid, polyethylene glycol 400, and purified water. The compound formulation comprises the following raw materials in parts by weight per 100 parts of the compound formulation: 2-5 parts of dimethicaine, 2-5 parts of trimecaine, 0.1-0.3 parts of chlorhexidine gluconate, 4-6 parts of Tween 80, 4-6 parts of oleic acid, 15-25 parts of polyethylene glycol 400, and the balance purified water. The present invention utilizes dimethicaine and trimecaine for compounding, which can effectively enhance the blocking effect, synergistically improve the anesthetic effect, reduce the dosage of anesthetic drugs, reduce side effects, and improve safety. Secondly, the present invention adds polyvinyl pyrrolidone K90, polyglycerol ester and ascorbic acid in a specific ratio to further improve the bioavailability of anesthetic drugs, enhance the anesthetic effect, and further improve the stability of anesthetic drugs.

Description

Technical Field

[0001] The present invention relates to the field of anesthetics, and in particular to a dimethocaine compound preparation and a preparation method thereof. Background Art

[0002] Local anesthetics play a vital role in medicine, particularly in surgery, dentistry, and other invasive procedures. Effective local anesthesia can significantly improve patient comfort and reduce postoperative pain and discomfort, thereby increasing treatment success rates and patient satisfaction. Local anesthetics include lidocaine, bupivacaine, prilocaine, chloroprocaine, dimethocaine, and trimecaine.

[0003] Dimethocaine is an aminoester local anesthetic with the advantages of rapid and long-lasting anesthetic effects. However, its relatively high toxicity and potential allergic reactions limit its widespread clinical application. Furthermore, the potential discomfort and side effects associated with topical application require attention.

[0004] Trimethocaine is a newer local anesthetic with good anesthetic efficacy and low toxicity, making it suitable for both local and topical anesthesia. While trimecaine has fewer side effects than dimethocaine, it may not provide the same intensity or duration of anesthesia as dimethocaine in some situations.

[0005] The physicochemical properties and pharmacological characteristics of dimethicaine and trimecaine are unique. Dimethicaine and trimecaine differ in chemical structure and pharmacological effects. When compounding, it is necessary to overcome compatibility and other issues to avoid adverse reactions or affect the efficacy.

[0006] Currently, there is a lack of systemic dimethocaine compound formulations on the market. Therefore, the development of a novel dimethocaine compound formulation has important clinical significance and application value. This compound formulation not only improves the reliability of local anesthesia but also has the potential to reduce pain and anxiety during surgery. Furthermore, optimized preparation methods will help improve the stability and biocompatibility of the drug, thereby providing a safe and effective new clinical option.

[0007] In summary, by developing a dimethocaine compound preparation, better effects can be achieved in local anesthesia, meeting the clinical demand for efficient and safe anesthetic drugs, which is of great significance to improving patients' treatment experience. Summary of the Invention

[0008] In view of this, the present invention provides a dimethocaine compound preparation and a preparation method thereof to solve the above problems.

[0009] The present invention can provide a rapid and effective anesthetic effect by compounding dimethocaine and trimecaine, and can also reduce toxicity and adverse reactions, thereby improving the safety and effectiveness of local anesthesia.

[0010] The technical solution of the present invention is achieved as follows:

[0011] A dimethicaine compound preparation contains the following raw materials in parts by weight per 100 parts of the compound preparation: 2-5 parts of dimethicaine and 2-5 parts of trimecaine.

[0012] A further technical solution is that the dimethocaine compound preparation contains chlorhexidine gluconate, Tween 80, oleic acid, polyethylene glycol 400, and purified water. Every 100 parts of the compound preparation include the following raw materials in parts by weight: 2-5 parts of dimethocaine, 2-5 parts of trimecaine, 0.1-0.3 parts of chlorhexidine gluconate, 4-6 parts of Tween 80, 4-6 parts of oleic acid, 15-25 parts of polyethylene glycol 400, and the balance purified water.

[0013] A further technical solution is that the dimethocaine compound preparation further contains a compounding auxiliary agent, and the compounding auxiliary agent is composed of the following components: polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid.

[0014] A further technical solution is that the mass ratio of polyvinylpyrrolidone K90, polyglycerol ester and ascorbic acid in the compound auxiliary agent is 1:1.5-2.5:6.5-7.5.

[0015] A further technical solution is that every 100 parts of the compound preparation includes the following raw materials in parts by weight: 2-5 parts of dimethocaine, 2-5 parts of trimecaine, 0.1-0.3 parts of chlorhexidine gluconate, 4-6 parts of Tween 80, 4-6 parts of oleic acid, 15-20 parts of polyethylene glycol 400, 1-2 parts of a compounding auxiliary agent, and the balance purified water.

[0016] The present invention also provides a method for preparing a dimethocaine compound preparation, comprising the following steps:

[0017] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0018] (2) Weigh the prescribed amount of dimethocaine and trimecaine and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B;

[0019] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH value to 6-9 with hydrochloric acid solution to obtain the target anesthetic solution.

[0020] The present invention also provides another method for preparing a dimethocaine compound formulation, comprising the following steps:

[0021] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0022] (2) Weigh the prescribed amount of dimethocaine, trimecaine, and compounding aids and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B;

[0023] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH value to 6-9 with hydrochloric acid solution to obtain the target anesthetic solution.

[0024] A further technical solution is that the concentration of the hydrochloric acid solution is 0.05-0.2 mol / L.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The dimethocaine compound preparation (concentration 2% to 5% + 2% to 5%) prepared by the present invention not only has a rapid anesthetic onset at a lower anesthetic drug concentration, but also can maintain a good anesthetic duration, thereby having a better comprehensive anesthetic effect.

[0027] The present invention utilizes a compound of dimethicaine and trimexacaine to effectively enhance the blocking effect, synergistically improve the anesthetic effect, reduce the dosage of anesthetic drugs, reduce side effects, and improve safety. Dimethicaine and trimexacaine may act together on sodium channels on nerve cell membranes through different mechanisms, thereby enhancing the blocking effect and prolonging the anesthesia duration. Due to its low toxicity, trimexacaine, when used in combination with dimethicaine, may help reduce the overall anesthetic dosage, thereby reducing the risk of side effects. Through synergistic action, dimethicaine and trimexacaine may maintain the anesthetic effect while reducing potential harm to the patient.

[0028] The invention adds polyvinyl pyrrolidone K90, polyglycerol ester and ascorbic acid in a specific ratio to further improve the bioavailability of anesthetic drugs, enhance the anesthetic effect, and further improve the stability of anesthetic drugs. DETAILED DESCRIPTION

[0029] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0030] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0031] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0032] Example 1 (concentration 4%+4%)

[0033] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 4 parts of dimethicaine, 4 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, and the balance purified water.

[0034] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0035] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0036] (2) Weigh the prescribed amount of dimethocaine and trimecaine and add them to solution A, heat to 40°C, and stir for 5 minutes to obtain solution B;

[0037] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0038] Example 2 (concentration 3%+3%)

[0039] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 3 parts of dimethicaine, 3 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, and the balance purified water.

[0040] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0041] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0042] (2) Weigh the prescribed amount of dimethocaine and trimecaine and add them to solution A, heat to 40°C, and stir for 5 minutes to obtain solution B;

[0043] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0044] Example 3 (concentration 2%+2%)

[0045] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 2 parts of dimethicaine, 2 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, and the balance purified water.

[0046] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0047] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0048] (2) Weigh the prescribed amount of dimethocaine and trimecaine and add them to solution A, heat to 40°C, and stir for 5 minutes to obtain solution B;

[0049] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0050] Example 4 (concentration 5%+5%)

[0051] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 5 parts of dimethicaine, 5 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, and the balance purified water.

[0052] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0053] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0054] (2) Weigh the prescribed amount of dimethocaine and trimecaine and add them to solution A, heat to 40°C, and stir for 5 minutes to obtain solution B;

[0055] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0056] Example 5 (concentration 2%+2%)

[0057] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 2 parts of dimethicaine, 2 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, 1.5 parts of a compounding auxiliary agent, and the balance purified water.

[0058] The above-mentioned dimethocaine compound preparation also contains a compounding auxiliary agent, which is composed of the following components: polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid. The mass ratio of polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid in the compounding auxiliary agent is 1:2:7.

[0059] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0060] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0061] (2) Weigh the prescribed amount of dimethocaine, trimecaine, and compounding aids and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B;

[0062] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0063] Example 6 (concentration 2%+2%)

[0064] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 2 parts of dimethicaine, 2 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, 1.0 part of a compounding auxiliary agent, and the balance purified water.

[0065] The above-mentioned dimethocaine compound preparation also contains a compounding auxiliary agent, which is composed of the following components: polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid. The mass ratio of polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid in the compounding auxiliary agent is 1:2:7.

[0066] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0067] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0068] (2) Weigh the prescribed amount of dimethocaine, trimecaine, and compounding aids and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B;

[0069] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0070] Example 7 (concentration 2%+2%)

[0071] A dimethicaine compound preparation comprises, per 100 parts of the compound preparation, the following raw materials in parts by weight: 2 parts of dimethicaine, 2 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, 2.0 parts of a compounding auxiliary agent, and the balance purified water.

[0072] The above-mentioned dimethocaine compound preparation also contains a compounding auxiliary agent, which is composed of the following components: polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid. The mass ratio of polyvinyl pyrrolidone K90, polyglycerol ester, and ascorbic acid in the compounding auxiliary agent is 1:2:7.

[0073] The preparation method of the above-mentioned dimethocaine compound preparation comprises the following steps:

[0074] (1) Weighing polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mixing and stirring to obtain solution A;

[0075] (2) Weigh the prescribed amount of dimethocaine, trimecaine, and compounding aids and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B;

[0076] (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH to 7.0 ± 0.5 with 0.1 mol / L hydrochloric acid solution to obtain the target anesthetic solution.

[0077] Comparative Example 1 (concentration 8%)

[0078] This comparative example differs from Example 1 primarily in that no dimethocaine is added. A trimecaine preparation is described, wherein 100 parts of the composite preparation comprises the following raw materials in parts by weight: 8 parts trimecaine, 0.2 parts chlorhexidine gluconate, 5 parts Tween 80, 5 parts oleic acid, 20 parts polyethylene glycol 400, and the balance purified water.

[0079] Comparative Example 2

[0080] A dimethocaine compound preparation is mainly different from Example 5 in that the mass ratio of polyvinylpyrrolidone K90, polyglycerol ester, and ascorbic acid in the compounding auxiliary agent is 1:1:1.

[0081] Comparative Example 3

[0082] A dimethicaine compound preparation differs from Example 5 primarily in that 100 parts of the compound preparation comprise the following raw materials in parts by weight: 2 parts of dimethicaine, 2 parts of trimecaine, 0.2 parts of chlorhexidine gluconate, 5 parts of Tween 80, 5 parts of oleic acid, 20 parts of polyethylene glycol 400, 3 parts of a compounding aid, and the balance purified water.

[0083] Test Example 1

[0084] Anesthetic: The dimethocaine compound preparations prepared in Example 3, Examples 5-7, and Comparative Examples 2-3 were test groups 1-6; the trimecaine preparation prepared in Comparative Example 1 was the control group.

[0085] 1.1 Experimental Methods: The anesthetic effects of the above-mentioned anesthetics on rats were tested using a radiant heat tail-flick latency test. The corresponding anesthetics and 0.9% saline samples were applied to the tails of rats in experimental groups 1-6 and the control group. The rats were then placed in a plastic box. The ventral surface of the distal 5-6 cm of the tail was placed over a 0.5 cm hole, under which an infrared radiator bulb was placed. A 10-s cutoff time was set (if the rat did not respond to the infrared radiator within 10 s, the experiment was terminated to avoid prolonged exposure that could cause tissue damage). The maximum possible effect (MPE) was calculated, and the baseline latency was calculated as the average of three different measurements taken at 10-min intervals.

[0086] MPE=(test latency-baseline latency) / (cutoff time-baseline latency)×100%.

[0087] 1.2 The test results are shown in Table 1.

[0088] Table 1 Anesthesia test results

[0089]

[0090] The results showed that compared with the control group (Comparative Example 1, concentration 8%), the dimethocaine composite preparations prepared in Examples 3 and 5 to 7 (concentration 2% + 2%), at a lower anesthetic drug concentration, not only had a rapid onset of anesthesia, but also was able to maintain a good duration of anesthesia, and had a better comprehensive anesthetic effect. The anesthetic effect of Examples 5 to 7 was better.

[0091] Test Example 2-Safety Test

[0092] 2.1 Test method

[0093] Healthy rabbits weighing 2.3-2.7 kg were selected and randomly divided into experimental groups 1 and 2 (corresponding to the dimethocaine compound formulations prepared in Examples 3 and 5, respectively). Each experimental group was divided into an intact skin group and a damaged skin group. Each group consisted of 10 rabbits, half male and half female. The day before the experiment, both sides of the rabbits' backs were depilated, with the hair removal area covering 3 cm*3 cm. In the intact skin group, the skin at the administration site in the depilated area was intact, undamaged, and normal. In the damaged skin group, the administration site in the depilated area was washed with warm water, disinfected, and scored with a sterile needle until bleeding was detected.

[0094] Using a left-right comparison test, 0.5 ml of the dimethocaine compound formulations prepared in Examples 3 and 5 were applied topically to one side of depilated skin. The other side was treated with lidocaine hydrochloride gel as a control. The administration site was covered with two layers of gauze (2.5 cm x 2.5 cm) and one layer of cellophane and secured with a non-irritating bandage. Rabbits were housed individually. Twenty-four hours after administration, the test substance was removed, and the administration site was cleaned with warm water. The administration site was visually observed and the presence of erythema and edema was recorded 1, 24, 48, and 72 hours after drug removal. Skin reactions were observed under natural light, scored according to the "Skin Irritation Reaction Scoring Criteria," and the average score was calculated and scored according to the "Skin Irritation Intensity Evaluation Criteria."

[0095] (1) Skin irritation reaction scoring criteria

[0096] Erythema grading: no erythema 0 point; mild erythema (barely visible) 1 point; moderate erythema (clearly visible)

[0097] 2 points; severe erythema 3 points; purple erythema to mild eschar formation 4 points.

[0098] Edema grading: no edema, 0 points; mild edema (barely visible), 1 point; moderate edema (obviously visible), 2 points; severe edema (skin bulge of about 1 mm with clear outline), 3 points; no erythema (skin bulge greater than 1 mm and expanding), 4 points.

[0099] (2) Skin irritation intensity evaluation standard: no irritation (0-0.49 points), mild irritation (0.5-2.99 points), moderate irritation (3.0-5.99 points), severe irritation (6.0-8.0 points).

[0100] 2.2 Test results

[0101] In the above tests, no erythema or edema was observed when the dimethocaine compound preparations prepared in Examples 3 and 5 were used, and there was no irritation to the skin, and there was no significant difference compared with the control.

[0102] Test Example 3-Stability Test

[0103] 3.1 Test Method: The dimethicaine compound preparations prepared in Examples 3 and 5 were subjected to stability tests (accelerated test and long-term test) to investigate the properties of the dimethicaine compound preparations, the dimethicaine and trimecaine contents, etc., wherein the dimethicaine and trimecaine contents were determined by HPLC.

[0104] Accelerated test: Place at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months, and take samples for testing at the 0th, 1st, 2nd, 3rd and 6th month.

[0105] Long-term test: Place at a temperature of 25℃±2℃ and a relative humidity of 60%±5% for 36 months, and take samples for testing at the 0th, 3rd, 6th, 9th, 12th, 18th, 24th and 36th month.

[0106] 3.2 Test results

[0107] Compared with the data from month 0, after 6 months of accelerated testing, the properties of the dimethicaine compound preparations prepared in Examples 3 and 5 did not change significantly, and there was no significant difference in the content of dimethicaine and trimecaine.

[0108] Compared with the data from month 0, the properties of the dimethicaine compound preparation prepared in Example 3 did not change significantly after 24 months of the long-term test, and there was no significant difference in the contents of dimethicaine and trimecaine.

[0109] Compared with the data at month 0, the properties of the dimethicaine compound preparation prepared in Example 5 did not change significantly after 36 months of the long-term test, and there was no significant difference in the contents of dimethicaine and trimecaine.

[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A dimethocaine compound preparation, characterized in that: Every 100 parts of the composite formulation is composed of the following raw materials in parts by weight: 2-5 parts of dimethocaine, 2-5 parts of trimecaine, 0.1-0.3 parts of chlorhexidine gluconate, 4-6 parts of Tween 80, 4-6 parts of oleic acid, 15-20 parts of polyethylene glycol 400, 1-2 parts of a compounding auxiliary, and the balance purified water; the compounding auxiliary is composed of the following components: polyvinylpyrrolidone K90, polyglycerol ester, and ascorbic acid; the mass ratio of polyvinylpyrrolidone K90, polyglycerol ester, and ascorbic acid in the compounding auxiliary is 1:1.5-2.5:6.5-7.

5.

2. The method for preparing the dimethocaine compound formulation according to claim 1, wherein The following steps are involved: (1) Weigh polyethylene glycol 400, oleic acid, Tween 80, and chlorhexidine gluconate according to the prescribed amount, mix and stir to obtain solution A; (2) Weigh the prescribed amount of dimethicaine, trimethicaine and compounding auxiliary agents and add them to solution A, heat to 35-40°C, and stir for 4-10 minutes to obtain solution B; (3) Weigh the prescribed amount of purified water and add it to solution B while stirring. After the purified water is added, adjust the pH value to 6-9 with hydrochloric acid solution to obtain the target anesthetic solution.

3. The preparation method of the dimethocaine compound formulation according to claim 2, wherein The concentration of the hydrochloric acid solution is 0.05-0.2 mol / L.

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