A composition containing ketorolac tromethamine and its sedative and analgesic application

Abstract

The invention belongs to the field of medical technology, and relates to a composition containing ketorolac tromethamine and a sedative and analgesic application. The anesthetic composition of the invention is composed of ketorolac tromethamine and eugenol. The two active ingredients of the invention show a strong synergistic effect, and the anesthetic effect of the composition after the two active ingredients are mixed is significantly improved compared with one of the active ingredients. Animal experiments show that the combined use of ketorolac tromethamine and eugenol has a stable anesthetic effect, the two active ingredients synergistically enhance the effect, reduce the toxic and side effects of the two active ingredients, and has good clinical application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a composition comprising ketorolac tromethamine and its sedative and analgesic application. Background Art

[0002] Anesthesia is a commonly used clinical medical method that uses drugs to paralyze or render the body unconscious, ensuring that various clinical medical operations can be performed smoothly and reducing or eliminating the patient's pain.

[0003] Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that can exert analgesic effects by inhibiting peripheral sensitization. Many research results show that it is better than morphine in relieving postoperative pain. Clinically, it is mainly used to treat severe pain after surgery and postpartum, pain in the middle and late stages of cancer, and moderate or severe external pain. Literature reports that the use of ketorolac tromethamine in preoperative anesthesia can improve the anesthetic effect and improve the patient's postoperative pain level (Zhang Shouchun. Application of ketorolac tromethamine injection in anesthesia for analgesia [J]. Journal of Qiqihar Medical College, 2013(17):2).

[0004] Eugenol is a naturally occurring compound reported to be present in a variety of plants, including cloves, ginger, cinnamon, turmeric, and chili peppers, as well as aromatic plants such as basil and nutmeg. Eugenol exhibits a variety of pharmacological activities, including antibacterial, anesthetic, antipyretic, antioxidant, and antitumor activities. my country's GB2760-2014 "National Food Safety Standard for the Use of Food Additives" specifies that eugenol, isoeugenol, and methyleugenol can be added to foods in appropriate amounts as synthetic flavorings. The U.S. Food and Drug Administration has also approved eugenol as a generally safe substance for use as a food additive, analgesic, and dental adhesive.

[0005] After searching, there is no related report in the prior art on the use of an anesthetic composition comprising ketorolac tromethamine and eugenol for anesthesia. Summary of the Invention

[0006] The invention provides an anesthetic composition with synergistic effect. The anesthetic composition has stable anesthetic effect and good sedative, analgesic and muscle relaxant effects.

[0007] A first aspect of the present invention provides an anesthetic composition comprising ketorolac tromethamine and eugenol, wherein the anesthetic composition is composed of ketorolac tromethamine and eugenol, and the weight ratio of the ketorolac tromethamine to eugenol is 1:3-5.

[0008] Preferably, the weight ratio of ketorolac tromethamine to eugenol in the anesthetic composition is 1:4.

[0009] The second aspect of the present invention provides a method for preparing the anesthetic composition described in the first aspect, comprising mixing the two active ingredients described in the first aspect.

[0010] The third aspect of the present invention provides an anesthetic pharmaceutical preparation, which comprises the anesthetic composition and a pharmaceutically acceptable carrier or excipient.

[0011] Preferably, the pharmaceutical preparation of the present invention is an oral preparation or an injectable preparation.

[0012] More preferably, the pharmaceutical preparation of the present invention is an injectable preparation.

[0013] More preferably, the injection preparation is an injection solution.

[0014] Furthermore, the anesthetic composition injection of the present invention contains 10 g of ketorolac tromethamine, 40 g of eugenol, 60 g of glycerol, 1.5 g of sodium bisulfite, 7 g of sodium chloride, and water for injection added to 2000 mL. The injection is prepared by the following method: taking a prescribed amount of glycerol, adding it to two-thirds of the prescribed amount of water for injection, and stirring it thoroughly to dissolve; then adding a prescribed amount of ketorolac tromethamine, and stirring it thoroughly to dissolve it; then adding the prescribed amount of eugenol, sodium bisulfite, and sodium chloride in sequence, stirring it thoroughly to dissolve it, replenishing the water for injection to the prescribed amount, filtering, sterilizing, and packaging.

[0015] Furthermore, the content detection method of the anesthetic composition injection of the present invention adopts high performance liquid chromatography, and the chromatographic conditions are: using octadecylsilane bonded silica gel as the filler; using methanol: water: and glacial acetic acid (51:44:5) as the mobile phase, the column temperature is 25°C, and the detection wavelength is 280nm.

[0016] The fourth aspect of the present invention provides use of the anesthetic composition described in the first aspect or the pharmaceutical preparation for anesthesia described in the third aspect in the preparation of anesthetic drugs.

[0017] Preferably, the anesthetic drug is a general anesthetic drug.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention provides a novel anesthetic composition comprising ketorolac tromethamine and eugenol, which has been found to exhibit significant synergistic effects in anesthesia. The two active ingredients of the present invention exhibit a strong synergistic effect, and the combined composition exhibits significantly enhanced anesthetic efficacy compared to either active ingredient alone.

[0020] The results of animal experiments show that the combined use of ketorolac tromethamine and eugenol has a rapid onset of action, stable anesthetic effect, and good sedative, analgesic and muscle relaxant effects. The two active ingredients synergistically enhance the effect and reduce the toxic and side effects of the two active ingredients, and have good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Comparison of the onset time of anesthesia in each group, compared with group A, * P<0.05; compared with group B, # P<0.05.

[0022] Figure 2 Comparison of the duration of anesthesia in each group, compared with group A, * P<0.05; compared with group B, # P<0.05.

[0023] Figure 3 Comparison of anesthesia recovery time in each group, compared with group A, * P<0.05; compared with group B, # P<0.05.

[0024] Figure 4 Comparison of anesthesia scores in each group, compared with group A, * P<0.05; compared with group B, # P<0.05. DETAILED DESCRIPTION

[0025] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work shall fall within the scope of protection of the present invention.

[0026] Example 1 Anesthetic composition injection of the present invention

[0027] Add ketorolac tromethamine 10g, eugenol 40g, glycerol 60g, sodium bisulfite 1.5g, sodium chloride 7g, and water for injection to 2000mL.

[0028] Preparation method: Take the prescribed amount of propylene glycol, add it to two-thirds of the prescribed amount of water for injection, and stir thoroughly to dissolve; then add the prescribed amount of ketorolac tromethamine, and stir thoroughly to dissolve; then add the prescribed amount of eugenol, sodium bisulfite, and sodium chloride in sequence, stir thoroughly to dissolve, add water for injection to the prescribed amount, filter, sterilize, and package.

[0029] Example 2 Anesthetic composition injection of the present invention

[0030] Add ketorolac tromethamine 10g, eugenol 30g, glycerol 48g, sodium bisulfite 1.5g, sodium chloride 7g, and water for injection to 2000mL.

[0031] Preparation method: Take the prescribed amount of propylene glycol, add it to two-thirds of the prescribed amount of water for injection, and stir thoroughly to dissolve; then add the prescribed amount of ketorolac tromethamine, and stir thoroughly to dissolve; then add the prescribed amount of eugenol, sodium bisulfite, and sodium chloride in sequence, stir thoroughly to dissolve, add water for injection to the prescribed amount, filter, sterilize, and package.

[0032] Example 3 Anesthetic composition injection of the present invention

[0033] Add ketorolac tromethamine 10g, eugenol 50g, glycerol 72g, sodium bisulfite 1.5g, sodium chloride 7g, and water for injection to 2000mL.

[0034] Preparation method: Take the prescribed amount of propylene glycol, add it to two-thirds of the prescribed amount of water for injection, and stir thoroughly to dissolve; then add the prescribed amount of ketorolac tromethamine, and stir thoroughly to dissolve; then add the prescribed amount of eugenol, sodium bisulfite, and sodium chloride in sequence, stir thoroughly to dissolve, add water for injection to the prescribed amount, filter, sterilize, and package.

[0035] Stability test

[0036] To demonstrate the excellent stability and safety of the anesthetic composition injection of the present invention, the anesthetic composition injection of the present invention was prepared according to Examples 1, 2, and 3, and sterilized by autoclaving at 115°C for 30 minutes. The anesthetic composition injection was then placed at room temperature, and samples were taken for inspection immediately after placement, 3, 6, 12, and 24 months after placement. The appearance of the samples was observed, and the contents of ketorolac tromethamine and eugenol were determined. High-performance liquid chromatography (HPLC) conditions for determining the contents of the two drugs in the anesthetic composition injection of the present invention were as follows: octadecylsilane bonded silica gel was used as the filler; a mobile phase of methanol:water:glacial acetic acid (51:44:5); a column temperature of 25°C; and a detection wavelength of 280 nm.

[0037] The test results are shown in Table 1.

[0038] Table 1 Results of room temperature stability test of the anesthetic composition injection of the present invention

[0039]

[0040]

[0041] When samples of the anesthetic composition injection of the present invention are kept at room temperature for a long time, the labeled amount of the active ingredient of the product does not change significantly, and the preparation is stable and reliable.

[0042] Efficacy Example 1 Anesthetic Effect of the Anesthetic Composition of the Present Invention on Rats

[0043] 1. Experimental Methods

[0044] Thirty SPF SD rats, half male and half female, weighing 180-200 g, were housed at room temperature of 20-25°C with free access to water and food.

[0045] The study included three dose groups of 10 mice each: the ketorolac tromethamine group (Group A) received an intraperitoneal injection of 10 mg / kg ketorolac tromethamine, the eugenol group (Group B) received an intraperitoneal injection of 10 mg / kg eugenol, and the combination group (Group C) received an intraperitoneal injection of 2 mg / kg ketorolac tromethamine plus 8 mg / kg eugenol. These drugs were formulated using polyethylene glycol 400.

[0046] Rats were intraperitoneally injected with the above dose. The timer was started after all the drug was injected, starting at this time (T0). The time until the righting reflex disappeared (T1) was recorded. Failure to achieve this was considered ineffective anesthesia. The time until the righting reflex returned (T2) and the time until the rat could stand and walk in a straight line (T3) were observed and recorded. T0-T1 is the time of anesthetic onset, T1-T2 is the duration of anesthesia, and T2-T3 is the time of anesthesia recovery.

[0047] After 15 minutes of anesthesia, the sedation score, analgesia score and muscle relaxation score were recorded.

[0048] The sedation scoring criteria are as follows: normal mental and behavioral status, no difference from before the test, 0 points; mild sedation (righting reflex persists, response to sound stimulation, lying on the side and being able to stand up and walk slowly again), 1 point; moderate sedation (righting reflex is delayed, response to sound stimulation is weakened, lying on the side with body tremors or turning over), 2 points; deep sedation (righting reflex disappears, no response to sound stimulation, lying on the side without moving), 3 points.

[0049] The analgesia scoring criteria are as follows: normal reaction to pain stimulation, 0 points; obvious reaction to tail clamping, pain reaction to clamping of both forelimbs and hindlimbs, and weakened pain reaction to acupuncture of the abdominal skin, 1 point; limb twitching after tail clamping, disappearance of pain reaction to clamping of forelimbs and hindlimbs, and disappearance of pain reaction to acupuncture of the abdominal skin, 2 points; no reaction to tail clamping, disappearance of pain reaction to clamping of forelimbs and hindlimbs, and disappearance of pain reaction to acupuncture of the abdominal skin, 3 points.

[0050] The muscle relaxation scoring criteria are: normal turning reflex, normal walking, tense abdominal wall muscles, 0 points; normal turning reflex, paddling of limbs, ability to crawl when stimulated, tense abdominal wall muscles, 1 point; slow turning reflex, slight paddling of limbs, trembling of abdominal wall muscles, 2 points; absent turning reflex, natural drooping of limbs, and obvious enlargement and relaxation of abdominal wall muscles, 3 points.

[0051] Anesthesia score = sedation score + analgesia score + muscle relaxation score.

[0052] 2. Statistical methods

[0053] Graphpad Prism 9.0 software was used for data processing and the measurement data were The comparison among multiple groups was performed by one-way analysis of variance, and the comparison between groups was performed by SNK-q. The difference was considered statistically significant when P < 0.05.

[0054] 3. Experimental Results

[0055] 3.1 Comparison of anesthesia time among groups

[0056] Compared with the single-use group, the rats in the combination group all experienced loss of righting reflex, and the onset time of anesthesia was significantly shorter than that of the single-use group, with a statistically significant difference (P < 0.05). The duration of anesthesia and anesthesia recovery time in the combination group were significantly longer than those in the single-use group, with a statistically significant difference (P < 0.05). Figure 1-3 .

[0057] 3.2 Comparison of anesthesia scores among groups

[0058] The anesthesia score of the combination group was significantly longer than that of the single-use group, and the difference was statistically significant (P < 0.05). Figure 4 The sedative, analgesic and muscle relaxant effects of the combination group were better than those of the single-use group.

[0059] This study combined ketorolac tromethamine and eugenol to shorten the anesthesia induction period, stabilize the anesthetic effect, and reduce the toxic side effects of the two active ingredients by synergistically enhancing their efficacy.

[0060] The above embodiments are merely examples for clarity of explanation and are not intended to limit the embodiments. Those skilled in the art will appreciate that other variations or modifications may be made based on the above description, and any such variations or modifications are still within the scope of protection of the present invention.

Claims

1. An anesthetic composition, characterized in that The anesthetic composition consists of ketorolac tromethamine and eugenol.

2. The anesthetic composition according to claim 1, characterized in that The weight ratio of ketorolac tromethamine to eugenol is 1:3-5.

3. The anesthetic composition according to claim 1, characterized in that The weight ratio of ketorolac tromethamine to eugenol is 1:

4.

4. A pharmaceutical preparation for anesthesia, characterized in that: The pharmaceutical preparation is prepared by mixing the anesthetic composition according to any one of claims 1 to 3 with pharmaceutically acceptable excipients.

5. The pharmaceutical preparation for anesthesia according to claim 4, characterized in that: The pharmaceutical preparation is an oral preparation or an injection preparation.

6. The pharmaceutical preparation for anesthesia according to claim 5, characterized in that: The injection preparation is an injection solution.

7. The pharmaceutical preparation for anesthesia according to claim 6, characterized in that: The injection contains 10 g of ketorolac tromethamine, 40 g of eugenol, 60 g of glycerol, 1.5 g of sodium bisulfite, 7 g of sodium chloride, and water for injection added to 2000 mL; The preparation method of the injection is as follows: take a prescribed amount of propylene glycol, add it to two-thirds of the prescribed amount of water for injection, and stir it thoroughly to dissolve; then add a prescribed amount of ketorolac tromethamine, and stir it thoroughly to dissolve it; then add the prescribed amounts of eugenol, sodium bisulfite, and sodium chloride in sequence, stir it thoroughly to dissolve it, add water for injection to the prescribed amount, filter, sterilize, and package.

8. The pharmaceutical preparation for anesthesia according to claim 7, characterized in that: The content detection method of the injection adopts high performance liquid chromatography, and the chromatographic conditions are: using octadecylsilane bonded silica gel as filler; using methanol: water: glacial acetic acid (51:44:5) as mobile phase, column temperature is 25°C, and detection wavelength is 280nm.

9. Use of the anesthetic composition according to any one of claims 1 to 3 or the pharmaceutical preparation for anesthesia according to claim 4 in the preparation of anesthetic drugs.

10. The use according to claim 9, characterized in that The anesthetic drug is a general anesthetic drug.

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