Oral mucosa administration sedation maintaining medicament and preparation method thereof

Abstract

The invention belongs to the field of preparation of sedation maintaining agents, and particularly relates to a sedation maintaining agent administrated through oral mucosa and a preparation method of the sedation maintaining agent. Bamboo leaf polysaccharide and pigskin collagen peptide are heated and mixed with chlorogenic acid and butyl acetate under the catalytic action of lanthanum nitrate, and the obtained moisturizing adhesive has biocompatibility, can be stably adhered to oral mucosa and can promote salivary secretion of children; nanoparticles obtained through freeze spray drying are uniformly dispersed in a copolymer solution containing sodium salicylate and polyacrylate, and the obtained nervous system regulator can balance excitability of sympathetic nerves and parasympathetic nerves of children; the emotion relieving composition contains modified felwort powder obtained through esterification reaction, the modified felwort powder is mixed with a moisturizing adhesive and a nervous system regulator, and the prepared sedation maintaining medicament administrated through the oral mucosa protects oral health of children in the oral operation anesthesia process, is free of irritation, improves anxiety emotion and does not affect postoperative awakening.

Description

Technical Field

[0001] The present invention belongs to the field of preparation of sedation-maintaining medicines, and specifically refers to a sedation-maintaining medicine administered via oral mucosa and a preparation method thereof. Background Art

[0002] Due to the high incidence of caries due to tooth structure such as enamel hypoplasia or enamel demineralization and improper oral hygiene care, the carious area of ​​the teeth has reached the pulp. Too many teeth require root canal treatment, causing severe pain and discomfort in the teeth and surrounding tissues. Local anesthesia is required to relieve the pain and discomfort during the operation.

[0003] For children who are highly afraid, anxious, and uncooperative of dental treatment, and special children with intellectual disability, autism, cerebral palsy, etc., local anesthesia is not effective and general anesthesia is required. A common complication during the recovery period after general anesthesia is a state of dysfunction of the higher nervous center characterized by increased excitability. Children often show impaired cognitive function, restlessness, tension and fear, which leads to the inadvertent removal of intravenous catheters, drainage tubes and dressings, seriously damaging the physical and mental health of children. Therefore, the use of sedatives together with anesthetics has positive significance for the prevention and treatment of children's nervous center dysfunction.

[0004] At present, the existing sedation maintenance drug preparation technology mainly has the following problems: First, the existing sedation maintenance drugs cannot maintain the moisture of the oral cavity. During caries surgery, the mouth needs to be opened for a long time, which leads to decreased oral muscle tension and dry mouth. Children's oral mucosa is thin and rich in blood vessels, and the salivary glands are not fully developed. Dry mouth can cause oral mucosal damage and infection; Second, children's brain nervous system development is unbalanced, the sympathetic nerve excitability is strong, and the parasympathetic nerve excitability is weak. After taking sedation maintenance drugs, there is strong irritation, the quality of postoperative awakening is poor, and the children are in a state of limb fatigue and depression for a long time; Third, after taking existing sedation maintenance drugs, they will interfere with children's central nervous system and digestive system, causing nausea and vomiting reactions. Summary of the invention

[0005] In view of the above situation, in order to overcome the defects of the prior art, the present invention provides a sedation-maintaining agent for administration through the oral mucosa and a preparation method thereof. In order to solve the problems that the existing sedation-maintaining agents cause dryness of the child's mouth, damage the child's oral mucosa, are highly irritating, the quality of children's postoperative awakening is poor, and cause nausea and vomiting, the present invention uses a moisturizing adhesive and a nervous system regulator mixed with a mood-soothing composition. The prepared sedation-maintaining agent for administration through the oral mucosa keeps the child's mouth moist, maintains the health of the oral mucosa, gently regulates the child's brain nerve function, does not damage the child's intestines, and does not cause nausea and vomiting.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows: the present invention proposes a sedation maintenance agent for oral mucosal administration, comprising the following components in parts by weight: 30-50 parts of moisturizing adhesive, 21-26 parts of nervous system regulator, 30-40 parts of gentian, 36-43 parts of tea fruit oil, 1.5-2.3 parts of sodium hypophosphite, 5-10 parts of L-menthol, 8-12 parts of lignan glycosides, 7-9 parts of pyridoxine, and 6-11 parts of bradykinin.

[0007] Preferably, the raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 23-27 parts of bamboo leaf polysaccharide, 20-25 parts of pig skin collagen peptide, 2.8-3.2 parts of lanthanum nitrate, 7-10 parts of methyl trifluoromethanesulfonate, 9-12 parts of carbachol, 1.6-2.3 parts of ferrous sulfate, 7-11 parts of chlorogenic acid, and 9-10 parts of butyl acetate.

[0008] Preferably, the raw materials for preparing the nervous system regulator include the following components in parts by weight: 11-14 parts of apigenin, 16-19 parts of bovine serum albumin, 15-18 parts of sodium salicylate, 10-15 parts of polyacrylate, 5-7 parts of lupeol, and 4-6 parts of monosialotetrahexosylganglioside.

[0009] Preferably, the method for preparing the moisturizing adhesive comprises the following steps: S1. Put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 2.4-3.5 kW, the reaction temperature is 70-80°C, the reaction speed is 60-80 r / min, the reaction time is 1.8-2.5 h, and the mixture is reacted to obtain a highly moisturizing complex; S2, placing methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water in a reactor with a power of 2.4-3.5 kW, the reaction temperature is 130-150°C, the reaction speed is 60-80 r / min, the reaction time is 1.2-1.4 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 30-38°C for 20-30 min at a speed of 300-500 r / min for sufficient adsorption to obtain a moisturizing adhesive.

[0010] Furthermore, in S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0011] Furthermore, in S2, the mass fraction of carbachol in ultrapure water is 5-10%.

[0012] Preferably, the preparation method of the nervous system regulator comprises the following steps: L1. Place apigenin and anhydrous ethanol in a stirring tank with a power of 1.4-1.8 kW, stir at a temperature of 70-80°C, at a speed of 80-100 r / min, for 15-20 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 1.8-2.4 kW, the constant temperature stirring temperature is 30-38°C, the constant temperature stirring time is 1.3-1.6 h, and the constant temperature stirring speed is 150-230r / min to obtain a complex solution; L3: Sodium salicylate, polyacrylate, ethyl acetate and ultrapure water are placed in a reactor with a power of 2.4-3.5 kW, the reaction temperature is 75-85°C, the reaction speed is 120-160 r / min, the reaction time is 2-3 h, and after the reaction, the temperature is kept at 50-65°C for 2-2.5 h to obtain a copolymer solution; L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a stirrer with a power of 1.2-1.6 kW, the stirring temperature is 50-60°C, the stirring time is 20-28 min, the stirring speed is 120-140 r / min, and after dissolving, add them to the complex solution prepared in L2, put them into a vacuum freeze-nano spray dryer with a power of 2.3-2.8 kW, the vacuum degree is -0.05 MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 2.5-3 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0013] Furthermore, in L1, the mass fraction of the apigenin in anhydrous ethanol is 34-38%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 2-4%.

[0014] Furthermore, in L3, the mass fraction of the sodium salicylate in ultrapure water is 17-24%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 18-21%.

[0015] The present invention also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 20-30 kW, a vacuum degree of 2-5 Pa, a freezing temperature of -65°C, a freezing time of 12-13 h, then heating to 2-4°C, drying for 5-6.5 h, to obtain freeze-dried gentian; Step 2, putting the freeze-dried gentian prepared in step 1 into an ultrafine grinder with a power of 5.5-6.5 kW, the grinding speed is 4600-5300 r / min, the grinding particle size is 0.2-0.4 mm, the grinding temperature is 25-28°C, the grinding time is 30-45min, and after grinding, it is mixed with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, and put into a constant temperature stirrer with a power of 1.8-2.4 kW, the stirring temperature is 50-70°C, the stirring speed is 80-100 r / min, the stirring time is 12-14 h, and the mixture is mixed for esterification reaction modification to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution in a stirrer with a power of 1.6-2.2 kW, stir at a temperature of 23-28°C, stir at a speed of 80-100 r / min, and stir for 12-14 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a temperature of 23-28°C, stir at a speed of 80-100 r / min, and stir for 18-26 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 23-28°C, at a speed of 80-100 r / min, for 20-30 min, and stir evenly to obtain a sedation-maintaining agent for oral mucosal administration.

[0016] Preferably, in step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0017] Preferably, in step three, the solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0018] The beneficial effects achieved by the present invention are as follows: The present invention proposes that the hydroxyl and carboxyl groups in the bamboo leaf polysaccharide and the pig skin collagen peptide form coordination bonds with the lanthanum ions in the lanthanum nitrate under the catalytic action of lanthanum nitrate, thereby forming a complex. The obtained highly moisturizing complex has antioxidant activity, stability, and strong water retention. Carbachol can excite the parasympathetic nerves, thereby releasing acetylcholine, acting on the salivary glands to secrete a large amount of thin saliva. Methyl trifluoromethanesulfonate and carbachol undergo a methylation reaction under the catalytic action of ferrous sulfate. The obtained modified carbachol is not easily inactivated by cholinesterase in the blood, thereby prolonging the action time of carbachol, improving the fat solubility of carbachol, promoting its absorption in the oral cavity, and having the effect of Sympathetic nerve excitement can also dilate the blood vessels of the salivary glands, further promoting the secretion of saliva. Chlorogenic acid not only has antioxidant ability, but can also combine with phospholipids on the cell membrane of oral cells to increase the permeability of the cell membrane. The highly moisturizing complex, modified carbachol solution, chlorogenic acid and butyl acetate with moisturizing effect are mixed. The prepared moisturizing adhesive has good biocompatibility, can stably adhere to the oral mucosa, effectively promote the secretion of saliva in children's mouths, keep the mouth moist, and has a long-lasting and efficient effect. Apigenin can inhibit the secretion of norepinephrine. Apigenin solution is mixed with bovine serum albumin to form a complex through hydrogen bonds, which can play a sustained release role, protect drug activity, increase drug solubility and bioavailability. The utilization rate is high. Sodium salicylate and modified carbachol work synergistically to promote the release of acetylcholine from children's parasympathetic nerve endings and inhibit the hydrolysis of acetylcholine. The carboxyl group in sodium salicylate reacts with the amino group and other functional groups in polyacrylate to generate ester bonds or amide bonds to form a cross-linked copolymer solution. After drying, the copolymer solution forms a film to keep the mouth moist and inhibit the evaporation of saliva. Lupeol reduces the permeability of nerve cell membranes to calcium ions, reducing the number of nerve-exciting ions entering cells. Apigenin cooperates with lupeol to inhibit the excitement of children's sympathetic nerves. It is mixed with monosialotetrahexosylganglioside, which has the function of protecting and nourishing nerve cells, and added to the complex solution. The obtained nanoparticles are evenly dispersed in the copolymer solution. The obtained nerve Systemic regulators can balance the excitability of children's sympathetic and parasympathetic nerves; the menthol contained in the mood-relief composition has a refreshing mint aroma; the modified gentian powder with excellent biocompatibility and biodegradability after synergistic esterification reaction is efficiently absorbed by oral cells and enters the blood circulation to relieve emotions and eliminate mental stress before and after surgery; pyridoxine contains pyridoxal and pyridoxine, which can promote the synthesis of brain neurotransmitters γ-aminobutyric acid that inhibit vomiting; bradykinin synergistically with modified gentian powder can increase the permeability of blood vessel walls, which not only accelerates the absorption of drugs, but also promotes the transportation of blood in blood vessels, so that the brain is adequately supplied with blood and the quality of postoperative recovery is high; lignan glycosides synergistically with tea fruit oil can repair the regeneration of damaged oral epithelial cells;The sedative maintenance agent administered through the oral mucosa protects the healthy oral mucosa of children during oral surgery anesthesia, is non-irritating, does not affect the anesthesia effect, improves preoperative and postoperative anxiety, ensures adequate cerebral blood supply, improves the quality of post-anesthesia awakening, reduces the occurrence of stress reactions, does not cause nausea and vomiting, is convenient for medication, can be wiped off after the operation, and avoids long-term effects. ; BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the present invention or the technical solutions in the prior art, the following will be described in a clear and understandable manner in conjunction with the accompanying drawings. Obviously, the drawings described below are only for the present invention, and for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 This is a graph showing the change rate of moisture content in the inner wall of the mouse oral cavity as described in Experimental Example 1 of the present invention; Figure 2 This is a graph showing the results of the norepinephrine content in mice described in Experimental Example 2 of the present invention; Figure 3 This is a graph showing the acetylcholine content in mice described in Experimental Example 2 of the present invention; Figure 4 This is a graph showing the results of the γ-aminobutyric acid content in mice described in Experimental Example 2 of the present invention; Figure 5 This is a graph showing the sedative effect on mice described in Experimental Example 3 of the present invention. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0022] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0023] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials and test strains used in the following examples are purchased from commercial channels unless otherwise specified.

[0024] Example 1: This example provides a sedation-maintaining agent for oral mucosal administration and a preparation method thereof. The sedation-maintaining agent for oral mucosal administration comprises the following components in parts by weight: 30 parts of moisturizing adhesive, 21 parts of nervous system regulator, 30 parts of gentian, 36 parts of tea fruit oil, 1.5 parts of sodium hypophosphite, 5 parts of L-menthol, 8 parts of lignan glycosides, 7 parts of pyridoxine, and 6 parts of bradykinin.

[0025] The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 23 parts of bamboo leaf polysaccharide, 20 parts of pig skin collagen peptide, 2.8 parts of lanthanum nitrate, 7 parts of methyl trifluoromethanesulfonate, 9 parts of carbachol, 1.6 parts of ferrous sulfate, 7 parts of chlorogenic acid, and 9 parts of butyl acetate.

[0026] The raw materials for preparing the nervous system regulator include the following components in parts by weight: 11 parts of apigenin, 16 parts of bovine serum albumin, 15 parts of sodium salicylate, 10 parts of polyacrylate, 5 parts of lupeol, and 4 parts of monosialotetrahexosylganglioside.

[0027] The preparation method of the moisturizing adhesive specifically comprises the following steps: S1. Put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 2.4 kW, the reaction temperature is 70°C, the reaction speed is 60 r / min, the reaction time is 1.8 h, and mixed reaction is performed to obtain a highly moisturizing complex; S2, put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reactor with a power of 2.4 kW, the reaction temperature is 130°C, the reaction speed is 60 r / min, the reaction time is 1.2 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 30°C for 20 min at a speed of 300 r / min for sufficient adsorption to obtain a moisturizing adhesive.

[0028] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0029] In S2, the mass fraction of carbachol in ultrapure water is 5%.

[0030] The preparation method of the nervous system regulator specifically comprises the following steps: L1. Place apigenin and anhydrous ethanol into a stirring tank with a power of 1.4 kW, stir at a temperature of 70°C, a stirring speed of 80 r / min, and a stirring time of 15 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 1.8 kW, the constant temperature stirring temperature is 30°C, the constant temperature stirring time is 1.3 h, and the constant temperature stirring speed is 150 r / min to obtain a complex solution; L3: Sodium salicylate, polyacrylate, ethyl acetate and ultrapure water were placed in a reactor with a power of 2.4 kW. The reaction temperature was 75°C, the reaction speed was 120 r / min and the reaction time was 2 h. After the reaction, the mixture was kept at 50°C for 2 h to obtain a copolymer solution. L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a 1.2 kW stirrer, the stirring temperature is 50°C, the stirring time is 20 min, the stirring speed is 120 r / min, and after dissolving, add them into the complex solution prepared in L2, put them into a 2.3 kW vacuum freeze-nano spray dryer, the vacuum degree is -0.05MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 2.5 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0031] In L1, the mass fraction of the apigenin in anhydrous ethanol is 34%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 2%.

[0032] In L3, the mass fraction of the sodium salicylate in ultrapure water is 17%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 18%.

[0033] This embodiment also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 20 kW, a vacuum degree of 2 Pa, a freezing temperature of -65°C, a freezing time of 12 h, then heating to 2°C, and drying for 5 h to obtain freeze-dried gentian; Step 2: Put the freeze-dried gentian prepared in step 1 into an ultrafine grinder with a power of 5.5 kW, the grinding speed is 4600 r / min, the grinding particle size is 0.2 mm, the grinding temperature is 25°C, and the grinding time is 30 min. After grinding, mix it with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, put it into a constant temperature stirrer with a power of 1.8 kW, the stirring temperature is 50°C, the stirring speed is 80 r / min, the stirring time is 12 h, and the mixture is mixed for esterification reaction modification to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution into a 1.6 kW stirrer at a stirring temperature of 23° C., a stirring speed of 80 r / min, and a stirring time of 12 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a stirring temperature of 23° C., a stirring speed of 80 r / min, and a stirring time of 18 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 23°C, a speed of 80 r / min, and a stirring time of 20 min, and stir evenly to obtain a sedation-maintaining agent for oral mucosal administration.

[0034] In step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0035] In step three, the solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0036] Example 2: This example provides a sedation-maintaining agent for oral mucosal administration and a preparation method thereof. The sedation-maintaining agent for oral mucosal administration comprises the following components in parts by weight: 40 parts of moisturizing adhesive, 23 parts of nervous system regulator, 35 parts of gentian, 41 parts of tea fruit oil, 2.1 parts of sodium hypophosphite, 8 parts of L-menthol, 10 parts of lignan glycosides, 8 parts of pyridoxine, and 9 parts of bradykinin.

[0037] The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 25 parts of bamboo leaf polysaccharide, 23 parts of pig skin collagen peptide, 3 parts of lanthanum nitrate, 8 parts of methyl trifluoromethanesulfonate, 11 parts of carbachol, 1.9 parts of ferrous sulfate, 9 parts of chlorogenic acid, and 9.5 parts of butyl acetate.

[0038] The raw materials for preparing the nervous system regulator include the following components in parts by weight: 12 parts of apigenin, 18 parts of bovine serum albumin, 16 parts of sodium salicylate, 13 parts of polyacrylate, 6 parts of lupeol, and 5 parts of monosialotetrahexosylganglioside.

[0039] The preparation method of the moisturizing adhesive specifically comprises the following steps: S1, put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 2.9 kW, the reaction temperature is 75°C, the reaction speed is 70 r / min, the reaction time is 2.2 h, and mixed reaction is performed to obtain a highly moisturizing complex; S2, put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reactor with a power of 2.8 kW, the reaction temperature is 140°C, the reaction speed is 70 r / min, the reaction time is 1.3 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 34°C for 25 min at a stirring speed of 400 r / min to allow sufficient adsorption to obtain a moisturizing adhesive.

[0040] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0041] In S2, the mass fraction of carbachol in ultrapure water is 8%.

[0042] The preparation method of the nervous system regulator specifically comprises the following steps: L1. Place apigenin and anhydrous ethanol in a stirring tank with a power of 1.6 kW, stir at a temperature of 75°C, a stirring speed of 90 r / min, and a stirring time of 18 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 2.2 kW, the constant temperature stirring temperature is 34°C, the constant temperature stirring time is 1.5 h, and the constant temperature stirring speed is 180 r / min to obtain a complex solution; L3: Sodium salicylate, polyacrylate, ethyl acetate and ultrapure water were placed in a reactor with a power of 3.2 kW. The reaction temperature was 80°C, the reaction rate was 140 r / min and the reaction time was 2.5 h. After the reaction, the temperature was kept at 55°C for 2.3 h to obtain a copolymer solution. L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a 1.4 kW stirrer, the stirring temperature is 55°C, the stirring time is 25 min, the stirring speed is 130 r / min, and after dissolving, add them into the complex solution prepared in L2, put them into a vacuum freeze-nano spray dryer with a power of 2.6 kW, the vacuum degree is -0.05MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 2.8 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0043] In L1, the mass fraction of the apigenin in anhydrous ethanol is 36%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 3%.

[0044] In L3, the mass fraction of the sodium salicylate in ultrapure water is 19%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 20%.

[0045] This embodiment also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 25 kW, a vacuum degree of 3 Pa, a freezing temperature of -65°C, a freezing time of 12 h, then heating to 3°C, and drying for 6 h to obtain freeze-dried gentian; Step 2: Put the freeze-dried gentian prepared in step 1 into an ultrafine grinder with a power of 6 kW, the grinding speed is 4900 r / min, the grinding particle size is 0.3 mm, the grinding temperature is 26°C, and the grinding time is 35 min. After grinding, mix it with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, put it into a constant temperature stirrer with a power of 2.1 kW, the stirring temperature is 60°C, the stirring speed is 90 r / min, the stirring time is 13 h, and the mixture is mixed for esterification reaction modification to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution into a 1.9 kW stirrer at a stirring temperature of 26°C, a stirring speed of 90 r / min, and a stirring time of 13 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a stirring temperature of 26°C, a stirring speed of 90 r / min, and a stirring time of 22 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 26°C, a stirring speed of 90 r / min, and a stirring time of 25 min, and stir evenly to obtain a sedation-maintaining agent for administration through the oral mucosa.

[0046] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0047] The solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0048] Example 3: This example provides a sedation-maintaining agent for oral mucosal administration and a preparation method thereof. The sedation-maintaining agent for oral mucosal administration comprises the following components in parts by weight: 50 parts of moisturizing adhesive, 26 parts of nervous system regulator, 40 parts of gentian, 43 parts of tea fruit oil, 2.3 parts of sodium hypophosphite, 10 parts of L-menthol, 12 parts of lignan glycosides, 9 parts of pyridoxine, and 11 parts of bradykinin.

[0049] The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 27 parts of bamboo leaf polysaccharide, 25 parts of pig skin collagen peptide, 3.2 parts of lanthanum nitrate, 10 parts of methyl trifluoromethanesulfonate, 12 parts of carbachol, 2.3 parts of ferrous sulfate, 11 parts of chlorogenic acid, and 10 parts of butyl acetate.

[0050] The raw materials for preparing the nervous system regulator include the following components in parts by weight: 14 parts of apigenin, 19 parts of bovine serum albumin, 18 parts of sodium salicylate, 15 parts of polyacrylate, 7 parts of lupeol, and 6 parts of monosialotetrahexosylganglioside.

[0051] The preparation method of the moisturizing adhesive specifically comprises the following steps: S1, put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 3.5 kW, the reaction temperature is 80°C, the reaction speed is 80 r / min, the reaction time is 2.5 h, and mixed reaction is performed to obtain a highly moisturizing complex; S2, put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reactor with a power of 3.5 kW, the reaction temperature is 150°C, the reaction speed is 80 r / min, the reaction time is 1.4 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 38°C for 30 min at a stirring speed of 500 r / min to allow sufficient adsorption to obtain a moisturizing adhesive.

[0052] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0053] In S2, the mass fraction of carbachol in ultrapure water is 10%.

[0054] The preparation method of the nervous system regulator specifically comprises the following steps: L1. Place apigenin and anhydrous ethanol in a stirring tank with a power of 1.8 kW, stir at a temperature of 80°C, a stirring speed of 100 r / min, and a stirring time of 20 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 2.4 kW, the constant temperature stirring temperature is 38°C, the constant temperature stirring time is 1.6 h, and the constant temperature stirring speed is 230 r / min to obtain a complex solution; L3: Sodium salicylate, polyacrylate, ethyl acetate and ultrapure water were placed in a reactor with a power of 3.5 kW. The reaction temperature was 85°C, the reaction rate was 160 r / min and the reaction time was 3 h. After the reaction, the mixture was kept at 65°C for 2.5 h to obtain a copolymer solution. L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a 1.6 kW stirrer, the stirring temperature is 60°C, the stirring time is 28 min, the stirring speed is 140 r / min, and after dissolving, add them into the complex solution prepared in L2, put them into a vacuum freeze-nano spray dryer with a power of 2.8 kW, the vacuum degree is -0.05MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 3 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0055] In L1, the mass fraction of apigenin in anhydrous ethanol is 38%, and in L2, the mass fraction of bovine serum albumin in ultrapure water is 4%.

[0056] In L3, the mass fraction of the sodium salicylate in ultrapure water is 24%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 21%.

[0057] This embodiment also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 30 kW, a vacuum degree of 5 Pa, a freezing temperature of -65°C, a freezing time of 13 h, then heating to 4°C, and drying for 6.5 h to obtain freeze-dried gentian; Step 2, the freeze-dried gentian prepared in step 1 is placed in an ultrafine grinder with a power of 6.5 kW, the grinding speed is 5300 r / min, the grinding particle size is 0.4 mm, the grinding temperature is 28°C, and the grinding time is 45 min. After grinding, it is mixed with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, and placed in a constant temperature stirrer with a power of 2.4 kW, the stirring temperature is 70°C, the stirring speed is 100 r / min, and the stirring time is 14 h. The mixture is modified by esterification reaction to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution in a 2.2 kW stirrer at a stirring temperature of 28° C., a stirring speed of 100 r / min, and a stirring time of 14 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a stirring temperature of 28° C., a stirring speed of 100 r / min, and a stirring time of 26 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 28°C, a stirring speed of 100 r / min, and a stirring time of 30 min, and stir evenly to obtain a sedation-maintaining agent for administration through the oral mucosa.

[0058] In step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0059] In step three, the solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0060] Example 4: This example provides a sedation-maintaining agent for oral mucosal administration and a preparation method thereof. The sedation-maintaining agent for oral mucosal administration comprises the following components in parts by weight: 35 parts of moisturizing adhesive, 22 parts of nervous system regulator, 32 parts of gentian, 39 parts of tea fruit oil, 1.8 parts of sodium hypophosphite, 6 parts of L-menthol, 9 parts of lignan glycosides, 7.5 parts of pyridoxine, and 8 parts of bradykinin.

[0061] The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 24 parts of bamboo leaf polysaccharide, 22 parts of pig skin collagen peptide, 2.9 parts of lanthanum nitrate, 7.5 parts of methyl trifluoromethanesulfonate, 10 parts of carbachol, 1.7 parts of ferrous sulfate, 8 parts of chlorogenic acid, and 9.3 parts of butyl acetate.

[0062] The raw materials for preparing the nervous system regulator include the following components in parts by weight: 11 parts of apigenin, 17 parts of bovine serum albumin, 15 parts of sodium salicylate, 12 parts of polyacrylate, 5 parts of lupeol, and 4.8 parts of monosialotetrahexosylganglioside.

[0063] The preparation method of the moisturizing adhesive specifically comprises the following steps: S1, put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 2.6 kW, the reaction temperature is 73°C, the reaction speed is 60 r / min, the reaction time is 1.9 h, and mixed reaction is performed to obtain a highly moisturizing complex; S2, put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reactor with a power of 2.6 kW, the reaction temperature is 135°C, the reaction speed is 60 r / min, the reaction time is 1.2 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 32°C for 23 min at a stirring speed of 300 r / min to allow sufficient adsorption to obtain a moisturizing adhesive.

[0064] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0065] In S2, the mass fraction of carbachol in ultrapure water is 7%.

[0066] The preparation method of the nervous system regulator specifically comprises the following steps: L1. Place apigenin and anhydrous ethanol in a stirring tank with a power of 1.5 kW, stir at a temperature of 73°C, a stirring speed of 80 r / min, and a stirring time of 16 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 1.9 kW, the constant temperature stirring temperature is 32°C, the constant temperature stirring time is 1.4 h, and the constant temperature stirring speed is 160 r / min to obtain a complex solution; L3: Sodium salicylate, polyacrylate, ethyl acetate and ultrapure water were placed in a reactor with a power of 2.8 kW. The reaction temperature was 78°C, the reaction rate was 130 r / min and the reaction time was 2.2 h. After the reaction, the temperature was kept at 53°C for 2.1 h to obtain a copolymer solution. L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a 1.3 kW stirrer, the stirring temperature is 52°C, the stirring time is 23 min, the stirring speed is 120 r / min, and after dissolving, add them into the complex solution prepared in L2, put them into a 2.5 kW vacuum freeze-nano spray dryer, the vacuum degree is -0.05MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 2.6 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0067] In L1, the mass fraction of the apigenin in anhydrous ethanol is 35%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 3%.

[0068] In L3, the mass fraction of the sodium salicylate in ultrapure water is 18%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 19%.

[0069] This embodiment also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 23 kW, a vacuum degree of 2 Pa, a freezing temperature of -65°C, a freezing time of 12 h, then heating to 2°C, and drying for 5.5 h to obtain freeze-dried gentian; Step 2: Put the freeze-dried gentian prepared in step 1 into an ultrafine grinder with a power of 5.8 kW, the grinding speed is 4700 r / min, the grinding particle size is 0.3 mm, the grinding temperature is 25°C, and the grinding time is 33 min. After grinding, mix it with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, put it into a constant temperature stirrer with a power of 1.9 kW, the stirring temperature is 55°C, the stirring speed is 80 r / min, the stirring time is 12 h, and the mixture is modified by esterification reaction to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution into a 1.7 kW stirrer at a stirring temperature of 25°C, a stirring speed of 80 r / min, and a stirring time of 12 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a stirring temperature of 24°C, a stirring speed of 80 r / min, and a stirring time of 20 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 24°C, a speed of 80 r / min, and a stirring time of 23 min, and stir evenly to obtain a sedation-maintaining agent for administration through the oral mucosa.

[0070] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0071] The solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0072] Example 5: This example provides a sedation-maintaining agent for oral mucosal administration and a preparation method thereof. The sedation-maintaining agent for oral mucosal administration comprises the following components in parts by weight: 45 parts of moisturizing adhesive, 25 parts of nervous system regulator, 38 parts of gentian, 42 parts of tea fruit oil, 2.2 parts of sodium hypophosphite, 9 parts of L-menthol, 11 parts of lignan glycosides, 8.5 parts of pyridoxine, and 10 parts of bradykinin.

[0073] The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 26 parts of bamboo leaf polysaccharide, 24 parts of pig skin collagen peptide, 3.1 parts of lanthanum nitrate, 9 parts of methyl trifluoromethanesulfonate, 12 parts of carbachol, 2.1 parts of ferrous sulfate, 10 parts of chlorogenic acid, and 9.8 parts of butyl acetate.

[0074] The raw materials for preparing the nervous system regulator include the following components in parts by weight: 13 parts of apigenin, 19 parts of bovine serum albumin, 17 parts of sodium salicylate, 14 parts of polyacrylate, 6.5 parts of lupeol, and 5.8 parts of monosialotetrahexosylganglioside.

[0075] The preparation method of the moisturizing adhesive specifically comprises the following steps: S1. Put bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water into a reactor with a power of 3.2 kW, the reaction temperature is 78°C, the reaction speed is 80 r / min, the reaction time is 2.3 h, and mixed reaction is performed to obtain a highly moisturizing complex; S2, put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reactor with a power of 3.2 kW, the reaction temperature is 150°C, the reaction speed is 80 r / min, the reaction time is 1.4 h, and the mixture is mixed for methylation reaction to obtain a modified carbachol solution; S3. Place the highly moisturizing complex prepared by S1 into the modified carbachol solution prepared by S2, and then add chlorogenic acid and butyl acetate. Stir at a temperature of 37°C for 28 min at a stirring speed of 500 r / min to allow sufficient adsorption to obtain a moisturizing adhesive.

[0076] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0077] In S2, the mass fraction of carbachol in ultrapure water is 9%.

[0078] The preparation method of the nervous system regulator specifically comprises the following steps: L1. Place apigenin and anhydrous ethanol in a stirring tank with a power of 1.7 kW, stir at a temperature of 78°C, a stirring speed of 100 r / min, and a stirring time of 19 min, and stir to mix to obtain an apigenin solution; L2, put bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 into a constant temperature stirring tank with a power of 2.3 kW, the constant temperature stirring temperature is 36°C, the constant temperature stirring time is 1.6 h, and the constant temperature stirring speed is 210 r / min to obtain a complex solution; L3 put sodium salicylate, polyacrylate, ethyl acetate and ultrapure water into a reactor with a power of 3.4 kW, the reaction temperature was 83°C, the reaction speed was 150 r / min, the reaction time was 2.8 h, after the reaction, the temperature was kept at 60°C for 2.4 h to obtain a copolymer solution; L4, put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a 1.5 kW stirrer, the stirring temperature is 58°C, the stirring time is 26 min, the stirring speed is 140 r / min, and after dissolving, add them into the complex solution prepared in L2, put them into a vacuum freeze-nano spray dryer with a power of 2.7 kW, the vacuum degree is -0.05MPa, the freeze-nano spray drying temperature is -40°C, the freeze-nano spray drying particle size is 100 nm, the freeze-nano spray drying time is 2.9 h, and freeze-spray drying is performed to prepare nanoparticles; L5. Put the nanoparticles prepared by L4 into the copolymer solution prepared by L3, and put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20,000 r / min, a stirring temperature of 25°C, a stirring time of 10 min, and disperse them evenly to obtain a nervous system regulator.

[0079] In L1, the mass fraction of apigenin in anhydrous ethanol is 37%, and in L2, the mass fraction of bovine serum albumin in ultrapure water is 4%.

[0080] In L3, the mass fraction of the sodium salicylate in ultrapure water is 22%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 21%.

[0081] This embodiment also provides a method for preparing a sedation-maintaining agent for oral mucosal administration, which specifically comprises the following steps: Step 1, placing the gentian in a vacuum freeze dryer with a power of 28 kW, a vacuum degree of 4 Pa, a freezing temperature of -65°C, a freezing time of 13 h, then heating to 4°C, and drying for 6.2 h to obtain freeze-dried gentian; Step 2: Put the freeze-dried gentian prepared in step 1 into an ultrafine grinder with a power of 6.2 kW, the grinding speed is 5100 r / min, the grinding particle size is 0.3 mm, the grinding temperature is 27°C, and the grinding time is 40 min. After grinding, mix with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, put into a constant temperature stirrer with a power of 2.2 kW, the stirring temperature is 65°C, the stirring speed is 100 r / min, the stirring time is 13.5 h, and mix for esterification modification to obtain modified gentian powder; Step 3: Place L-menthol, lignan glycosides, pyridoxine, bradykinin and 50% ethanol solution in a 2.1 kW stirrer at a stirring temperature of 27° C., a stirring speed of 100 r / min, and a stirring time of 14 min. After dissolving, add the modified gentian powder prepared in step 2, stir at a temperature of 27° C., a stirring speed of 100 r / min, and a stirring time of 25 min to mix and obtain a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir at a temperature of 27°C, a stirring speed of 100 r / min, and a stirring time of 28 min, and stir evenly to obtain a sedation-maintaining agent for administration through the oral mucosa.

[0082] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0083] The solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0084] Experimental Example 1: Determination of the ability of oral cavity moisturizing and saliva secretion promotion in mice.

[0085] The test steps for determining the ability of the sedation-maintaining agent prepared in Examples 1-5 to moisturize the oral cavity and promote saliva secretion in mice are as follows: (1) 42 Kunming mice weighing 25 g were selected and randomly divided into 6 groups, with 7 mice in each group. The inner wall of the oral cavity was smeared with 0.1 g of the sedation maintenance agent prepared in Examples 1-5 for oral mucosal administration on the left side of the inner wall of the oral cavity of the mice in groups 1 to 5 using a sterile applicator stick. 0.1 g of alprazolam agent was smeared on the left side of the inner wall of the oral cavity as the CK control group. The inner wall of the oral cavity of each group of mice was tested for moisture data using a skin moisture meter Real Bubee. (2) On the first day, the left side of the oral cavity of mice was first smeared with the sedation maintenance agent prepared in Example and administered through the oral mucosa. The moisture data of the oral cavity were collected 10 min, 20 min, 30 min, 40 min, 50 min, and 60 min after the oral mucosa was administered. The moisture content change rate (%) was calculated according to the formula: (moisture content value of the left side of the oral cavity - moisture content value of the right side of the oral cavity) / moisture content value of the right side of the oral cavity × 100%. The higher the value, the stronger the ability to moisturize and promote saliva secretion.

[0086] Experimental Example 2: Mouse blood index determination test.

[0087] The experimental steps for determining the effect of the sedation-maintaining agent prepared in Examples 1-5 and administered via the oral mucosa on the blood indexes of mice are as follows: (1) 42 Kunming mice weighing 25 g were selected and randomly divided into 6 groups, with 7 mice in each group. The mice in groups 1 to 5 of Experimental Examples were smeared with 0.2 g of the sedation maintenance agent prepared in Examples 1 to 5 for oral mucosal administration using a sterile applicator stick. The mice in groups 1 to 5 were smeared with 0.2 g of 0.9% saline as the CK control group. The oral walls of the mice in each group were smeared at 8:00 a.m. every day, once a day, for 7 consecutive days. (2) The mice were restrained in a 50 mL centrifuge tube, with a hole opened for ventilation and padding at the tail to prevent the mice from moving freely in the tube without causing external injuries. Starting from the third day after the application of the sedation-maintaining agent prepared in Example 1-5 and administered via the oral mucosa, the mice were restrained for 3 hours 1 hour after administration every day for 7 consecutive days to obtain anxious mice; (3) The mice were dislocated by neck and blood was collected. 0.5 mL of blood was collected from the retro-orbital venous plexus of the mice. The blood was allowed to stand for 30 min and then centrifuged at 3500 r / min for 15 min to separate the serum. The mouse norepinephrine kit (purchased from ELISA, catalog number: YJ11269), acetylcholine assay kit (purchased from ELISA, catalog number: ml093046) and γ-aminobutyric acid assay kit (purchased from ELISA, catalog number: ml092747) were used to measure the levels of norepinephrine, acetylcholine and γ-aminobutyric acid in the mice.

[0088] Experimental Example 3: Test for measuring sedative effect on anxious mice.

[0089] The experimental steps for determining the sedative effect of the oral mucosal sedative maintenance agent prepared in Examples 1-5 on anxiety model mice are as follows: (1) 42 Kunming mice weighing 25 g were selected and randomly divided into 6 groups, with 7 mice in each group. The mice in groups 1 to 5 of Experimental Examples were smeared with 0.2 g of the sedation maintenance agent prepared in Examples 1 to 5 for oral mucosal administration using a sterile applicator stick. The mice in groups 1 to 5 were smeared with 0.2 g of 0.9% saline as the CK control group. The oral walls of the mice in each group were smeared at 8:00 a.m. every day, once a day, for 7 consecutive days. (2) The mice were restrained in a 50 mL centrifuge tube, with a hole opened for ventilation and padding at the tail to prevent the mice from moving freely in the tube without causing external injuries. Starting from the third day after the application of the sedation-maintaining agent prepared in Example 1-5 and administered via the oral mucosa, the mice were restrained for 3 hours 1 hour after administration every day for 7 consecutive days to obtain anxious mice; (3) In the EPM device, two open arms and two closed arms are placed opposite each other in a cross shape. The length and width of each arm are 15 cm × 41 cm respectively, and there is a platform in the center of the connecting arms. The maze is 30 cm above the ground and the height of the closed arms is 12 cm. The experiment is carried out under dark conditions. At the beginning of the experiment, the anxious mice are placed in the maze from the central grid to the closed arms, and their activities are recorded within 5 minutes. The recorded indicators include: the time and number of times they enter the open arms, and the time and number of times they enter the closed arms. One anxious mouse is tested each time in the same device. After the test is completed and the anxious mice are taken out, the maze is cleaned and 10% ethanol is sprayed to remove the odor. The evaluation indicators of the anxiety level of the experimental animals are: Ratio of times of entering open arms = times of entering open arms / (times of entering open arms + times of entering closed arms) × 100%; The ratio of time to enter open arm = time to enter open arm / (time to enter open arm + time to enter closed arm) × 100%.

[0090] Result analysis: Figure 1This is a graph showing the change rate of moisture content in mice described in Experimental Example 1 of the present invention. As shown in the figure, after the sedation-maintaining agent administered via the oral mucosa described in Examples 1-5 was applied to the left side of the inner wall of the mouse's oral cavity, the change rate of moisture content in the mouse was 5.37%, 6.42%, 7.56%, 8.69%, 9.46%, and 9.97%, and the moisture content gradually increased, while the change rate of moisture content in the inner wall of the oral cavity of the mice in the control group was 0.46%, 0.35%, 0.27%, 0.14%, 0.08%, and 0.02%, and the moisture content gradually decreased, indicating that the sedation-maintaining agent administered via the oral mucosa of the present invention not only has a good moisturizing effect, but also can stimulate the secretion of saliva in the oral cavity, further maintain the moisture of the oral environment, and protect the health of the oral mucosa.

[0091] Figure 2 This is a result graph of the norepinephrine content in mice described in Experimental Example 2 of the present invention. As shown in the figure, the sedation-maintaining agent administered via the oral mucosa described in Examples 1-5 was applied to the inner wall of the oral cavity of anxious mice. The norepinephrine content in the anxious mice was 0.64 ng / g, 0.59 ng / g, 0.54 ng / g, 0.58 ng / g, and 0.56 ng / g, while the norepinephrine content in the anxious mice of the control group was 1.75 ng / g. Figure 3 This is a result graph of the acetylcholine content in mice described in Experimental Example 2 of the present invention. As shown in the figure, the sedation-maintaining agent administered via the oral mucosa described in Examples 1-5 was applied to the inner wall of the oral cavity of anxious mice. The acetylcholine content in the anxious mice was 245 nmol / L, 249 nmol / L, 261 nmol / L, 250nmol / L, and 254 nmol / L, while the acetylcholine content in the anxious mice of the control group was 155 nmol / L. Figure 4 This is a result graph of the γ-aminobutyric acid content in mice described in Experimental Example 2 of the present invention. As shown in the figure, the sedation-maintaining agent administered through the oral mucosa described in Examples 1-5 was smeared on the inner wall of the oral cavity of anxious mice. The γ-aminobutyric acid content in the anxious mice was 19.34 mg / g, 22.79 mg / g, 25.34 mg / g, 24.54 mg / g, and 23.23 mg / g, while the γ-aminobutyric acid content in the anxious mice in the control group was 8.45 mg / g, indicating that the sedation-maintaining agent administered through the oral mucosa of the present invention can balance the excitability of the sympathetic and parasympathetic nerves, effectively play a sedative role, and enhance the synthesis of γ-aminobutyric acid, a brain neurotransmitter that inhibits vomiting, to avoid the occurrence of nausea and vomiting symptoms.

[0092] Figure 5This is a graph showing the sedative effect on mice described in Experimental Example 3 of the present invention. As shown in the figure, the sedative maintenance agent administered via the oral mucosa as described in Examples 1-5 was applied to the inner wall of the oral cavity of anxious mice. The number of times the anxious mice entered the open arms was 43.73%, 45.86%, 47.42%, 46.4%, and 45.95%, and the time spent in the open arms was 41.35%, 43.49%, 44.57%, 43.85%, and 44.55%, while the number of times the anxious mice in the control group entered the open arms was 31.65%, and the time spent in the open arms was 24.61%, indicating that the sedative maintenance agent administered via the oral mucosa of the present invention can significantly improve the occurrence of anxious behavior.

[0093] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

[0094] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. A sedation-maintaining agent for oral mucosal administration, characterized in that: The sedation-maintaining agent for oral mucosal administration specifically comprises the following components in parts by weight: 30-50 parts of moisturizing adhesive, 21-26 parts of nervous system regulator, 30-40 parts of gentian, 36-43 parts of tea fruit oil, 1.5-2.3 parts of sodium hypophosphite, 5-10 parts of L-menthol, 8-12 parts of lignan glycosides, 7-9 parts of pyridoxine, and 6-11 parts of bradykinin; The raw materials for preparing the moisturizing adhesive include the following components in parts by weight: 23-27 parts of bamboo leaf polysaccharide, 20-25 parts of pig skin collagen peptide, 2.8-3.2 parts of lanthanum nitrate, 7-10 parts of methyl trifluoromethanesulfonate, 9-12 parts of carbachol, 1.6-2.3 parts of ferrous sulfate, 7-11 parts of chlorogenic acid, and 9-10 parts of butyl acetate; The raw materials for preparing the nervous system regulator include the following components in parts by weight: 11-14 parts of apigenin, 16-19 parts of bovine serum albumin, 15-18 parts of sodium salicylate, 10-15 parts of polyacrylate, 5-7 parts of lupeol, and 4-6 parts of monosialotetrahexosylganglioside.

2. The sedation-maintaining agent for oral mucosal administration according to claim 1, characterized in that: The preparation method of the moisturizing adhesive specifically comprises the following steps: S1, mixing bamboo leaf polysaccharide, pig skin collagen peptide, lanthanum nitrate and ultrapure water to obtain a highly moisturizing complex; S2, mixing methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water and reacting them to obtain a modified carbachol solution; S3, placing the highly moisturizing complex prepared in S1 into the modified carbachol solution prepared in S2, and then adding chlorogenic acid and butyl acetate, stirring for sufficient adsorption to obtain a moisturizing adhesive.

3. The sedation-maintaining agent for oral mucosal administration according to claim 2, characterized in that: In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

4. The sedation-maintaining agent for oral mucosal administration according to claim 3, characterized in that: In S2, the mass fraction of carbachol in ultrapure water is 5-10%.

5. The sedation-maintaining agent for oral mucosal administration according to claim 4, characterized in that: The preparation method of the nervous system regulator specifically comprises the following steps: L1. Dissolve apigenin in anhydrous ethanol with stirring to obtain an apigenin solution; L2, stirring and mixing bovine serum albumin, ultrapure water and the apigenin solution prepared in L1 to obtain a complex solution; L3: mixing sodium salicylate with polyacrylate, ethyl acetate and ultrapure water to obtain a copolymer solution; L4, stirring and dissolving lupeol, monosialotetrahexosylganglioside and 70% ethanol solution, adding them to the complex solution prepared in L2, and freeze-spray drying to prepare nanoparticles; L5. Evenly dispersing the nanoparticles prepared by L4 in the copolymer solution prepared by L3 to obtain a nervous system regulator.

6. The sedation-maintaining agent for oral mucosal administration according to claim 5, characterized in that: In L1, the mass fraction of the apigenin in anhydrous ethanol is 34-38%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 2-4%.

7. The sedation-maintaining agent for oral mucosal administration according to claim 6, characterized in that: In L3, the mass fraction of the sodium salicylate in ultrapure water is 17-24%, and in L4, the mass fraction of the polyacrylate in ethyl acetate is 18-21%.

8. A method for preparing the sedation-maintaining agent for oral mucosal administration according to any one of claims 1 to 7, characterized in that: The specific steps include: Step 1, freeze-drying the gentian to obtain freeze-dried gentian; Step 2, crushing the freeze-dried gentian prepared in step 1, mixing with tea fruit oil, sodium hypophosphite and N-methylpyrrolidone, and stirring to react to obtain modified gentian powder; Step 3, dissolving L-menthol, lignan glycosides, pyridoxine, and bradykinin in a 50% ethanol solution, adding the dissolved gentian powder prepared in step 2 to mix, and obtaining a mood-relief composition; Step 4: Add the moisturizing adhesive and the nervous system regulator to the mood-relief composition prepared in step 3, stir evenly, and obtain a sedation-maintaining agent for administration through the oral mucosa.

9. The method for preparing the sedation-maintaining agent for oral mucosal administration according to claim 8, characterized in that: In step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.

6.

10. The method for preparing the sedation-maintaining agent for oral mucosal administration according to claim 9, characterized in that: In step three, the solid-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

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