A sedative maintenance agent for oral mucosal administration and its preparation method

Abstract

The present invention belongs to the field of preparation of sedative maintenance agents, and particularly relates to a sedative maintenance agent for oral mucosal administration and a preparation method thereof. Bamboo leaf polysaccharide and porcine skin 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 and can stably adhere to the oral mucosa to promote saliva secretion in children; the nanoparticles obtained by freeze spray drying are uniformly dispersed in a copolymer solution containing sodium salicylate and polyacrylate, and the obtained nervous system regulator can balance the excitability of the sympathetic nerve and the parasympathetic nerve in children; the soothing mood composition contains modified gentian powder obtained by esterification reaction, and is mixed with the moisturizing adhesive and the nervous system regulator. The sedative maintenance agent for oral mucosal administration prepared thereby protects oral health during oral surgery anesthesia in children, has no irritation, improves anxiety mood, and does not affect postoperative awakening.

Description

Technical Field

[0001] The present invention belongs to the field of preparation of sedative maintenance agents, and specifically refers to a sedative maintenance agent for oral mucosal administration and a preparation method thereof. Background Art

[0002] Due to dental structure problems such as enamel hypoplasia or enamel demineralization, and improper oral hygiene care, the incidence of dental caries is high. The carious parts of the teeth have reached the dental pulp, and there are too many teeth that need root canal treatment, resulting in strong 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 fearful, anxious, and uncooperative with dental treatment, and special children such as those with mental retardation, autism, and cerebral palsy, the effect of local anesthesia is not good 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 mainly characterized by increased excitability. Children often show impaired cognitive function, restlessness, nervousness, and fear, resulting in accidental removal of intravenous catheters, drainage tubes, and dressings, which seriously damages the physical and mental health of children. Therefore, it is of positive significance to use sedatives together with anesthetics to prevent and treat the dysfunction of the children's nervous center.

[0004] Currently, the existing sedative maintenance agent preparation technologies mainly have the following problems: First, the existing sedative maintenance agents cannot maintain the moisture of the oral cavity. During the dental caries operation, the mouth needs to be opened for a long time, resulting in a decrease in oral muscle tension and oral dryness. The oral mucosa of children is thin and rich in blood vessels, and the salivary glands are underdeveloped. Oral dryness will cause oral mucosal damage and infection. Second, the development of the children's brain nervous system is unbalanced, with strong excitability of the sympathetic nerve and weak excitability of the parasympathetic nerve. After taking the sedative maintenance agent, the irritation is strong, and the quality of postoperative recovery is poor. Children are often in a state of weakness in the limbs and listlessness for a long time. Third, after taking the existing sedative maintenance agents, they will interfere with the central nervous system and digestive system of children, resulting in nausea and vomiting reactions. Summary of the Invention

[0005] In view of the above situation, in order to overcome the defects of the existing technology, the present invention provides a sedative maintenance agent for oral mucosal administration and a preparation method thereof. In order to solve the problems of oral dryness in children caused by the existing sedative maintenance agents, damage to the oral mucosa of children, strong irritation, poor quality of postoperative recovery in children, and nausea and vomiting, the present invention uses a moisturizing adhesive and a nervous system regulator to mix a soothing mood composition. The prepared sedative maintenance agent for oral mucosal administration can keep the oral cavity of children moist, maintain the health of the oral mucosa, gently regulate the brain nerve function of children, do not damage the intestines of children, and do not cause nausea and vomiting.

[0006] To achieve the above object, the technical solution adopted by the present invention is as follows. The present invention provides a sedative maintenance agent for oral mucosal administration, comprising the following components in parts by weight:

[0007] 30 - 50 parts of a moisturizing adhesive, 21 - 26 parts of a 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 lignin glycoside, 7 - 9 parts of pyridoxine, 6 - 11 parts of bradykinin.

[0008] Preferably, the preparation raw materials of the moisturizing adhesive comprise the following components in parts by weight: 23 - 27 parts of bamboo leaf polysaccharide, 20 - 25 parts of porcine 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, 9 - 10 parts of butyl acetate.

[0009] Preferably, the preparation raw materials of the nervous system regulator comprise 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, 4 - 6 parts of monosialotetrahexosylganglioside.

[0010] Preferably, the preparation method of the moisturizing adhesive specifically comprises the following steps:

[0011] S1. Put bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water into a reaction kettle with a power of 2.4 - 3.5 kW, a reaction temperature of 70 - 80 °C, a reaction speed of 60 - 80 r / min, and a reaction duration of 1.8 - 2.5 h, and carry out a mixed reaction to obtain a high-moisture complex;

[0012] S2. Put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water into a reaction kettle with a power of 2.4 - 3.5 kW, a reaction temperature of 130 - 150 °C, a reaction speed of 60 - 80 r / min, and a reaction duration of 1.2 - 1.4 h, and carry out a methylation reaction to obtain a modified carbachol solution;

[0013] S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, stir at a temperature of 30 - 38 °C for 20 - 30 min, and stir at a rotation speed of 300 - 500 r / min for sufficient adsorption to obtain the moisturizing adhesive.

[0014] Furthermore, in S1, the mass fraction of the bamboo leaf polysaccharide in the ultrapure water is 8%.

[0015] Further, in S2, the mass fraction of carbachol in ultrapure water is 5-10%.

[0016] Preferably, the preparation method of the nervous system regulator specifically comprises the following steps:

[0017] L1. Put apigenin and absolute ethanol into a stirring tank with a power of 1.4-1.8 kW, with a stirring temperature of 70-80 °C, a stirring speed of 80-100 r / min, and a stirring duration of 15-20 min, and stir and mix to obtain an apigenin solution;

[0018] 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, with a constant-temperature stirring temperature of 30-38 °C, a constant-temperature stirring duration of 1.3-1.6 h, and a constant-temperature stirring speed of 150-230 r / min to obtain a complex solution;

[0019] L3. Put sodium salicylate, polyacrylate, ethyl acetate and ultrapure water into a reaction kettle with a power of 2.4-3.5 kW, with a reaction temperature of 75-85 °C, a reaction speed of 120-160 r / min, and a reaction duration of 2-3 h. After the reaction, keep it warm at 50-65 °C for 2-2.5 h to obtain a copolymer solution;

[0020] L4. Put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a stirrer with a power of 1.2-1.6 kW, with a stirring temperature of 50-60 °C, a stirring duration of 20-28 min, and a stirring speed of 120-140 r / min. After dissolution, add it to the complex solution prepared in L2, and put it into a vacuum freeze nano spray dryer with a power of 2.3-2.8 kW, with a vacuum degree of -0.05 MPa, a freeze nano spray drying temperature of -40 °C, a freeze nano spray drying particle size of 100 nm, and a freeze nano spray drying duration of 2.5-3 h to carry out freeze spray drying to prepare and form nanoparticles;

[0021] L5. Put the nanoparticles prepared in L4 into the copolymer solution prepared in L3, put it into an ultrasonic stirrer with a power of 1.8 kW, with an ultrasonic frequency of 15 kHz, a stirring speed of 20000 r / min, a stirring temperature of 25 °C, and a stirring duration of 10 min, and disperse it evenly to obtain a nervous system regulator.

[0022] Further, in L1, the mass fraction of apigenin in absolute ethanol is 34-38%, and in L2, the mass fraction of bovine serum albumin in ultrapure water is 2-4%.

[0023] Further, in L3, the mass fraction of sodium salicylate in ultrapure water is 17 - 24%, and in L4, the mass fraction of polyacrylate in ethyl acetate is 18 - 21%.

[0024] The present invention also provides a preparation method of a sedative maintenance medicament for oral mucosal administration, which specifically includes the following steps:

[0025] Step 1: Put gentian into a vacuum freeze dryer with a power of 20 - 30 kW, a vacuum degree of 2 - 5 Pa, a freezing temperature of -65°C, and a freezing duration of 12 - 13 h. Then, raise the temperature to 2 - 4°C and dry for 5 - 6.5 h to obtain freeze-dried gentian.

[0026] Step 2: Put the freeze-dried gentian prepared in Step 1 into an ultrafine pulverizer with a power of 5.5 - 6.5 kW, a pulverizing rotation speed of 4600 - 5300 r / min, a pulverizing particle size of 0.2 - 0.4 mm, a pulverizing temperature of 25 - 28°C, and a pulverizing duration of 30 - 45 min. After pulverization, put it into a constant temperature stirrer with a power of 1.8 - 2.4 kW together with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone. Stir at a temperature of 50 - 70°C, a stirring rotation speed of 80 - 100 r / min, and a stirring duration of 12 - 14 h for esterification reaction modification to obtain modified gentian powder.

[0027] Step 3: Put L-menthol, lignin glycoside, pyridoxine, bradykinin, and 50% ethanol solution into a stirrer with a power of 1.6 - 2.2 kW. Stir at a temperature of 23 - 28°C, a stirring speed of 80 - 100 r / min, and a stirring duration of 12 - 14 min. After dissolution, put the modified gentian powder prepared in Step 2 into it, stir at a temperature of 23 - 28°C, a stirring speed of 80 - 100 r / min, and a stirring duration of 18 - 26 min for mixing to obtain a mood-relieving composition.

[0028] Step 4: Add a moisturizing adhesive and a nervous system regulator to the mood-relieving composition prepared in Step 3. Stir at a temperature of 23 - 28°C, a stirring speed of 80 - 100 r / min, and a stirring duration of 20 - 30 min until evenly stirred to obtain a sedative maintenance medicament for oral mucosal administration.

[0029] Preferably, in Step 2, the volume ratio of tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0030] Preferably, in Step 3, the material-liquid ratio of L-menthol to 50% ethanol solution is 1:1.4 g / mL.

[0031] The beneficial effects achieved by the present invention are as follows:

[0032] The present invention proposes that under the catalytic action of lanthanum nitrate, hydroxyl groups and carboxyl groups in bamboo leaf polysaccharide and porcine skin collagen peptide form coordination bonds with lanthanum ions in lanthanum nitrate, thereby forming a complex. The obtained high-moisture complex has antioxidant activity, stability, and strong water retention. Carbachol can excite the parasympathetic nerve, thereby releasing acetylcholine, which acts on the salivary gland to secrete a large amount of thin saliva. Methyl trifluoromethanesulfonate and carbachol undergo a methylation reaction under the catalytic action of ferrous sulfate. The modified carbachol obtained is not easily inactivated by cholinesterase in the blood, prolongs the action time of carbachol, improves the liposolubility of carbachol, promotes its absorption in the oral cavity, and the excitement of the parasympathetic nerve can also dilate the blood vessels of the salivary gland, further promoting the secretion of saliva. Chlorogenic acid not only has antioxidant ability, but also can bind to phospholipids on the cell membrane of oral cells, increasing the permeability of the cell membrane. Mixing the high-moisture complex, the modified carbachol solution, chlorogenic acid, and butyl acetate with moisturizing effect, the prepared moisturizing adhesive has good biocompatibility, can stably adhere to the oral mucosa, effectively promote the secretion of saliva in children's oral cavity, keep the oral cavity moist, and has a long-lasting and efficient effect; Apigenin can inhibit the secretion of norepinephrine. The apigenin solution is mixed with bovine serum albumin to form a complex through hydrogen bonds, which can play a sustained-release role, protect the drug activity, increase the solubility and bioavailability of the drug. Sodium salicylate and the modified carbachol act synergistically to promote the release of acetylcholine from the endings of children's parasympathetic nerves and inhibit the hydrolysis of acetylcholine. The carboxyl group in sodium salicylate reacts with functional groups such as amino groups in polyacrylate to form ester bonds or amide bonds, and the copolymer solution obtained by crosslinking forms a film after drying, keeping the oral cavity moist and inhibiting the evaporation of saliva. Lupeol reduces the permeability of the nerve cell membrane to calcium ions, reducing the number of ions that excite the nerve entering the cell. Apigenin and lupeol act synergistically to inhibit the excitement of children's sympathetic nerves. Mixed with monosialotetrahexosylganglioside with the function of protecting and nourishing nerve cells and added to the complex solution, the obtained nanoparticles are evenly dispersed in the copolymer solution, and the obtained nervous system regulator can balance the excitability of children's sympathetic and parasympathetic nerves; Menthol contained in the soothing mood composition has a cool mint aroma. Synergistically with the modified gentian powder with excellent biocompatibility and biodegradability after esterification reaction, it is efficiently absorbed by oral cells and enters the blood circulation to soothe the mood and eliminate the mental stress before and after surgery. Pyridoxine contains pyridoxal and pyridoxol, which can promote the synthesis of the brain neurotransmitter γ-aminobutyric acid that inhibits vomiting. Bradykinin and the modified gentian powder act synergistically to increase the permeability of the blood vessel wall, not only accelerating the absorption of the medicament, but also promoting the transportation of blood in the blood vessels, ensuring sufficient blood supply to the brain and high quality of postoperative awakening. Lignin glycoside and tea fruit oil act synergistically to repair the regeneration of damaged oral epithelial cells;The sedative maintenance agent prepared for transmucosal administration protects the oral mucosa of children during oral surgery anesthesia, is non-irritating, does not affect the anesthetic effect, improves preoperative and postoperative anxiety, has sufficient cerebral blood supply, has a high quality of recovery after anesthesia, reduces the occurrence of stress responses, does not cause nausea and vomiting symptoms, is convenient for drug application, can be wiped off after the operation, and avoids long-term effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following will be described in a clear and understandable manner in combination with the drawings. Obviously, the drawings in the following description are only those of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0034] Figure 1 It is a graph showing the change rate of the moisture content in the inner wall of the mouse oral cavity in Experimental Example 1 of the present invention;

[0035] Figure 2 It is a graph showing the content of norepinephrine in the mouse body in Experimental Example 2 of the present invention;

[0036] Figure 3 It is a graph showing the content of acetylcholine in the mouse body in Experimental Example 2 of the present invention;

[0037] Figure 4 It is a graph showing the content of γ-aminobutyric acid in the mouse body in Experimental Example 2 of the present invention;

[0038] Figure 5 It is a graph showing the sedative effect of the mouse in Experimental Example 3 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0039] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in combination with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a 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 those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0040] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the present invention. The preferred implementation methods and materials described herein are only for illustrative purposes and do not limit the content of this application.

[0041] The experimental methods in the following embodiments are all conventional methods unless otherwise specified; the test materials and test strains used in the following embodiments are all obtained from commercial channels unless otherwise specified.

[0042] Example 1: This example provides a sedative maintenance agent for oral mucosal administration and its preparation method. The sedative maintenance agent for oral mucosal administration includes the following components in parts by weight:

[0043] 30 parts of a moisture-retaining adhesive, 21 parts of a 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 glycoside, 7 parts of pyridoxine, and 6 parts of bradykinin.

[0044] The raw materials for preparing the moisture-retaining adhesive include the following components in parts by weight: 23 parts of bamboo leaf polysaccharide, 20 parts of porcine 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.

[0045] 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.

[0046] The preparation method of the moisture-retaining adhesive specifically includes the following steps:

[0047] S1. Put bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water into a reaction kettle with a power of 2.4 kW, a reaction temperature of 70 °C, a reaction speed of 60 r / min, and a reaction duration of 1.8 h, and carry out a mixed reaction to obtain a high-moisture complex;

[0048] S2. Put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water into a reaction kettle with a power of 2.4 kW, a reaction temperature of 130 °C, a reaction speed of 60 r / min, and a reaction duration of 1.2 h, and carry out a methylation reaction to obtain a modified carbachol solution;

[0049] S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, stir at a temperature of 30 °C for 20 min, and stir at a rotation speed of 300 r / min for sufficient adsorption to obtain a moisture-retaining adhesive.

[0050] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0051] In S2, the mass fraction of the carbachol in ultrapure water is 5%.

[0052] The preparation method of the nervous system regulator specifically includes the following steps:

[0053] L1. Put apigenin and absolute 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 duration of 15 min to obtain an apigenin solution through stirring and mixing;

[0054] 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, stir at a constant temperature of 30 °C for 1.3 h at a constant stirring speed of 150 r / min to obtain a complex solution;

[0055] L3. Put sodium salicylate, polyacrylate, ethyl acetate, and ultrapure water into a reaction kettle with a power of 2.4 kW, react at a temperature of 75 °C, a reaction speed of 120 r / min, and a reaction duration of 2 h. After the reaction, keep warm at 50 °C for 2 h to obtain a copolymer solution;

[0056] L4. Put lupeol, monosialotetrahexosylganglioside, and 70% ethanol solution into a stirrer with a power of 1.2 kW, stir at a temperature of 50 °C for 20 min at a stirring speed of 120 r / min. After dissolution, add it to the complex solution prepared in L2, and put it into a vacuum freeze nano spray dryer with a power of 2.3 kW, a vacuum degree of -0.05 MPa, a freeze nano spray drying temperature of -40 °C, a freeze nano spray drying particle size of 100 nm, and a freeze nano spray drying duration of 2.5 h to carry out freeze spray drying to prepare and form nanoparticles;

[0057] L5. Put the nanoparticles prepared in L4 into the copolymer solution prepared in L3, put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20000 r / min, and a stirring temperature of 25 °C, stir for 10 min to disperse evenly to obtain a nervous system regulator.

[0058] In L1, the mass fraction of apigenin in absolute ethanol is 34%. In L2, the mass fraction of bovine serum albumin in ultrapure water is 2%.

[0059] In L3, the mass fraction of sodium salicylate in ultrapure water is 17%. In L4, the mass fraction of polyacrylate in ethyl acetate is 18%.

[0060] This embodiment also provides a preparation method of a sedative maintenance agent for oral mucosal administration, which specifically includes the following steps:

[0061] Step 1: Put gentiana scabra bunge into a vacuum freeze dryer with a power of 20 kW, a vacuum degree of 2 Pa, a freezing temperature of -65°C, and a freezing duration of 12 h. Then heat it up to 2°C and dry for 5 h to obtain freeze-dried gentiana scabra bunge.

[0062] Step 2: Put the freeze-dried gentiana scabra bunge prepared in Step 1 into a superfine grinder with a power of 5.5 kW, a crushing rotation speed of 4600 r / min, a crushing particle size of 0.2 mm, a crushing temperature of 25°C, and a crushing duration of 30 min. After crushing, put it together with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone into a constant temperature stirrer with a power of 1.8 kW, a stirring temperature of 50°C, a stirring rotation speed of 80 r / min, and a stirring duration of 12 h for esterification reaction modification to obtain modified gentiana scabra bunge powder.

[0063] Step 3: Put L-menthol, lignan glycoside, pyridoxine, and bradykinin together with a 50% ethanol solution into a stirrer with a power of 1.6 kW, a stirring temperature of 23°C, a stirring speed of 80 r / min, and a stirring duration of 12 min. After dissolution, put in the modified gentiana scabra bunge powder prepared in Step 2, with a stirring temperature of 23°C, a stirring speed of 80 r / min, and a stirring duration of 18 min for mixing to obtain a mood-soothing composition.

[0064] Step 4: Add a moisturizing adhesive and a nervous system regulator to the mood-soothing composition prepared in Step 3, with a stirring temperature of 23°C, a stirring speed of 80 r / min, and a stirring duration of 20 min. Stir evenly to obtain a sedative maintenance medicament for oral mucosal administration.

[0065] In Step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0066] In Step 3, the material-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0067] Example 2: This example provides a sedative maintenance medicament for oral mucosal administration and its preparation method. The sedative maintenance medicament for oral mucosal administration includes the following components in parts by weight:

[0068] 40 parts of a moisturizing adhesive, 23 parts of a nervous system regulator, 35 parts of gentiana scabra bunge, 41 parts of tea fruit oil, 2.1 parts of sodium hypophosphite, 8 parts of L-menthol, 10 parts of lignan glycoside, 8 parts of pyridoxine, and 9 parts of bradykinin.

[0069] The preparation raw materials of the moisturizing adhesive include the following components in parts by weight: 25 parts of bamboo leaf polysaccharide, 23 parts of porcine 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.

[0070] 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.

[0071] The preparation method of the moisturizing adhesive specifically includes the following steps:

[0072] S1. Put bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water into a reaction kettle with a power of 2.9 kW, a reaction temperature of 75 °C, a reaction speed of 70 r / min, and a reaction duration of 2.2 h, and carry out a mixed reaction to obtain a high-moisture complex;

[0073] S2. Put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water into a reaction kettle with a power of 2.8 kW, a reaction temperature of 140 °C, a reaction speed of 70 r / min, and a reaction duration of 1.3 h, and carry out a methylation reaction by mixing to obtain a modified carbachol solution;

[0074] S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, stir at a temperature of 34 °C for 25 min, and stir at a rotation speed of 400 r / min for sufficient adsorption to obtain the moisturizing adhesive.

[0075] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0076] In S2, the mass fraction of the carbachol in ultrapure water is 8%.

[0077] The preparation method of the nervous system regulator specifically includes the following steps:

[0078] L1. Put apigenin and absolute ethanol into 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 duration of 18 min, and stir and mix to obtain an apigenin solution;

[0079] 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, stir at a constant temperature of 34 °C for 1.5 h, and stir at a constant-temperature stirring speed of 180 r / min to obtain a complex solution;

[0080] L3 puts sodium salicylate, polyacrylate, ethyl acetate, and ultrapure water into a reaction kettle with a power of 3.2 kW, a reaction temperature of 80 °C, a reaction speed of 140 r / min, and a reaction duration of 2.5 h. After the reaction, it is kept warm at 55 °C for 2.3 h to obtain a copolymer solution;

[0081] L4 puts lupeol, monosialotetrahexosylganglioside, and 70% ethanol solution into a stirrer with a power of 1.4 kW, a stirring temperature of 55 °C, a stirring duration of 25 min, and a stirring speed of 130 r / min. After dissolution, it is added to the complex solution prepared by L2 and put into a vacuum freeze nano spray dryer with a power of 2.6 kW, a vacuum degree of -0.05 MPa, a freeze nano spray drying temperature of -40 °C, a freeze nano spray drying particle size of 100 nm, and a freeze nano spray drying duration of 2.8 h for freeze spray drying to prepare nanoparticles;

[0082] L5 puts the nanoparticles prepared by L4 into the copolymer solution prepared by L3, puts it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20000 r / min, a stirring temperature of 25 °C, and a stirring duration of 10 min for uniform dispersion to obtain a nervous system regulator.

[0083] In L1, the mass fraction of apigenin in absolute ethanol is 36%, and in L2, the mass fraction of bovine serum albumin in ultrapure water is 3%.

[0084] In L3, the mass fraction of sodium salicylate in ultrapure water is 19%, and in L4, the mass fraction of polyacrylate in ethyl acetate is 20%.

[0085] This embodiment also provides a preparation method of a sedative maintenance agent for oral mucosal administration, specifically including the following steps:

[0086] Step 1: Put gentian into a vacuum freeze dryer with a power of 25 kW, a vacuum degree of 3 Pa, a freezing temperature of -65 °C, and a freezing duration of 12 h, and then heat it to 3 °C and dry it for 6 h to obtain freeze-dried gentian;

[0087] Step 2: Put the freeze-dried gentian grass prepared in Step 1 into an ultrafine pulverizer with a power of 6 kW, with a pulverizing rotation speed of 4,900 r / min, a pulverizing particle size of 0.3 mm, a pulverizing temperature of 26°C, and a pulverizing duration of 35 min. After pulverization, put it into a constant-temperature stirrer with a power of 2.1 kW together with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone. The stirring temperature is 60°C, the stirring rotation speed is 90 r / min, and the stirring duration is 13 h for esterification reaction modification to obtain modified gentian grass powder;

[0088] Step 3: Put L-menthol, lignan glycoside, pyridoxine, and bradykinin into a 50% ethanol solution in a stirrer with a power of 1.9 kW. The stirring temperature is 26°C, the stirring speed is 90 r / min, and the stirring duration is 13 min. After dissolution, put the modified gentian grass powder prepared in Step 2 into it. The stirring temperature is 26°C, the stirring speed is 90 r / min, and the stirring duration is 22 min for mixing to obtain a mood-soothing composition;

[0089] Step 4: Add a moisturizing adhesive and a nervous system regulator to the mood-soothing composition prepared in Step 3. The stirring temperature is 26°C, the stirring speed is 90 r / min, and the stirring duration is 25 min. Stir evenly to obtain a sedative maintenance medicament for oral mucosal administration.

[0090] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0091] The material-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0092] Example 3: This example provides a sedative maintenance medicament for oral mucosal administration and its preparation method. The sedative maintenance medicament for oral mucosal administration includes the following components in parts by weight:

[0093] 50 parts of moisturizing adhesive, 26 parts of nervous system regulator, 40 parts of gentian grass, 43 parts of tea fruit oil, 2.3 parts of sodium hypophosphite, 10 parts of L-menthol, 12 parts of lignan glycoside, 9 parts of pyridoxine, and 11 parts of bradykinin.

[0094] The preparation raw materials of the moisturizing adhesive include the following components in parts by weight: 27 parts of bamboo leaf polysaccharide, 25 parts of porcine 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.

[0095] The preparation raw materials of 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.

[0096] The preparation method of the moisturizing adhesive specifically comprises the following steps:

[0097] S1. Put bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate and ultrapure water into a reaction kettle with a power of 3.5 kW, with a reaction temperature of 80 °C, a reaction speed of 80 r / min and a reaction duration of 2.5 h, and carry out a mixing reaction to obtain a highly moisturizing complex;

[0098] S2. Put methyl trifluoromethanesulfonate, carbachol, ferrous sulfate and ultrapure water into a reaction kettle with a power of 3.5 kW, with a reaction temperature of 150 °C, a reaction speed of 80 r / min and a reaction duration of 1.4 h, and carry out a methylation reaction by mixing to obtain a modified carbachol solution;

[0099] S3. Put the highly moisturizing complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, with a stirring temperature of 38 °C, a stirring duration of 30 min and a stirring speed of 500 r / min, and carry out sufficient adsorption to obtain the moisturizing adhesive.

[0100] In S1, the mass fraction of the bamboo leaf polysaccharide in the ultrapure water is 8%.

[0101] In S2, the mass fraction of the carbachol in the ultrapure water is 10%.

[0102] The preparation method of the nervous system regulator specifically comprises the following steps:

[0103] L1. Put apigenin and absolute ethanol into a stirring tank with a power of 1.8 kW, with a stirring temperature of 80 °C, a stirring speed of 100 r / min and a stirring duration of 20 min, and carry out a stirring and mixing to obtain an apigenin solution;

[0104] 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, with a constant-temperature stirring temperature of 38 °C, a constant-temperature stirring duration of 1.6 h and a constant-temperature stirring speed of 230 r / min to obtain a complex solution;

[0105] L3. Put sodium salicylate, polyacrylate, ethyl acetate and ultrapure water into a reaction kettle with a power of 3.5 kW, with a reaction temperature of 85 °C, a reaction speed of 160 r / min and a reaction duration of 3 h, and after the reaction, keep the temperature at 65 °C for 2.5 h to obtain a copolymer solution;

[0106] L4. Put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a stirrer with a power of 1.6 kW, stir at a temperature of 60 °C for 28 min at a stirring speed of 140 r / min. After dissolution, add it to the complex solution prepared in L2, and put it into a vacuum freeze nano spray dryer with a power of 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, and the freeze nano spray drying time is 3 h for freeze spray drying to prepare nanoparticles;

[0107] L5. Put the nanoparticles prepared in L4 into the copolymer solution prepared in L3, and put it into an ultrasonic stirrer with a power of 1.8 kW. The ultrasonic frequency is 15 kHz, the stirring speed is 20000 r / min, the stirring temperature is 25 °C, and the stirring time is 10 min for uniform dispersion to obtain a nervous system regulator.

[0108] In L1, the mass fraction of apigenin in absolute ethanol is 38%, and in L2, the mass fraction of bovine serum albumin in ultrapure water is 4%.

[0109] In L3, the mass fraction of sodium salicylate in ultrapure water is 24%, and in L4, the mass fraction of polyacrylate in ethyl acetate is 21%.

[0110] This example also provides a preparation method of a sedative maintenance agent for oral mucosal administration, which specifically includes the following steps:

[0111] Step 1. Put gentian into a vacuum freeze dryer with a power of 30 kW, the vacuum degree is 5 Pa, the freezing temperature is -65 °C, and the freezing time is 13 h. Then heat up to 4 °C and dry for 6.5 h to obtain freeze-dried gentian;

[0112] Step 2. Put the freeze-dried gentian prepared in Step 1 into an ultrafine pulverizer with a power of 6.5 kW, the pulverizing speed is 5300 r / min, the pulverizing particle size is 0.4 mm, the pulverizing temperature is 28 °C, and the pulverizing time is 45 min. After pulverization, mix it with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, and put it into a constant temperature stirrer with a power of 2.4 kW. Stir at a temperature of 70 °C at a stirring speed of 100 r / min for 14 h for esterification reaction modification to obtain modified gentian powder;

[0113] Step 3: Put L-menthol, lignin glycoside, pyridoxine, bradykinin and 50% ethanol solution into a stirrer with a power of 2.2 kW, with a stirring temperature of 28°C, a stirring speed of 100 r / min, and a stirring duration of 14 min. After dissolution, add the modified gentian powder prepared in Step 2, with a stirring temperature of 28°C, a stirring speed of 100 r / min, and a stirring duration of 26 min for mixing to obtain a mood-soothing composition;

[0114] Step 4: Add a moisturizing adhesive and a nervous system regulator to the mood-soothing composition prepared in Step 3, with a stirring temperature of 28°C, a stirring speed of 100 r / min, and a stirring duration of 30 min, and stir evenly to obtain a sedative maintenance agent for oral mucosal administration.

[0115] In Step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0116] In Step 3, the material-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0117] Example 4: This example provides a sedative maintenance agent for oral mucosal administration and its preparation method. The sedative maintenance agent for oral mucosal administration includes the following components in parts by weight:

[0118] 35 parts of a moisturizing adhesive, 22 parts of a 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 lignin glycoside, 7.5 parts of pyridoxine, and 8 parts of bradykinin.

[0119] The preparation raw materials of the moisturizing adhesive include the following components in parts by weight: 24 parts of bamboo leaf polysaccharide, 22 parts of porcine 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.

[0120] The preparation raw materials of 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.

[0121] The preparation method of the moisturizing adhesive specifically includes the following steps:

[0122] S1: Put bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water into a reaction kettle with a power of 2.6 kW, with a reaction temperature of 73°C, a reaction speed of 60 r / min, and a reaction duration of 1.9 h for mixing reaction to obtain a high-moisture complex;

[0123] 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, and the reaction duration is 1.2 h. Mix them to carry out the methylation reaction to obtain the modified carbachol solution.

[0124] S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate. The stirring temperature is 32 °C, the stirring duration is 23 min, and the stirring speed is 300 r / min. Carry out sufficient adsorption to obtain the moisture-retaining adhesive.

[0125] In S1, the mass fraction of the bamboo leaf polysaccharide in ultrapure water is 8%.

[0126] In S2, the mass fraction of the carbachol in ultrapure water is 7%.

[0127] The preparation method of the nervous system regulator specifically includes the following steps:

[0128] L1. Put apigenin and absolute ethanol into a stirring tank with a power of 1.5 kW. The stirring temperature is 73 °C, the stirring speed is 80 r / min, and the stirring duration is 16 min. Stir and mix to obtain the apigenin solution.

[0129] 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 duration is 1.4 h, and the constant-temperature stirring speed is 160 r / min to obtain the complex solution.

[0130] L3. Put sodium salicylate, polyacrylate, ethyl acetate, and ultrapure water into a reactor with a power of 2.8 kW. The reaction temperature is 78 °C, the reaction speed is 130 r / min, and the reaction duration is 2.2 h. After the reaction, keep it warm at 53 °C for 2.1 h to obtain the copolymer solution.

[0131] L4. Put lupeol, monosialotetrahexosylganglioside, and 70% ethanol solution into a stirrer with a power of 1.3 kW. The stirring temperature is 52 °C, the stirring duration is 23 min, and the stirring speed is 120 r / min. After dissolution, add it to the complex solution prepared in L2, and put it into a vacuum freeze nano spray dryer with a power of 2.5 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, and the freeze nano spray drying duration is 2.6 h to carry out freeze spray drying to prepare and form nanoparticles.

[0132] L5. Put the nanoparticles prepared in L4 into the copolymer solution prepared in L3, and place them in 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, and a stirring duration of 10 min. After uniform dispersion, a nervous system regulator is obtained.

[0133] In L1, the mass fraction of apigenin in absolute ethanol is 35%. In L2, the mass fraction of bovine serum albumin in ultrapure water is 3%.

[0134] In L3, the mass fraction of sodium salicylate in ultrapure water is 18%. In L4, the mass fraction of polyacrylate in ethyl acetate is 19%.

[0135] This example also provides a preparation method of a sedative maintenance agent for oral mucosal administration, which specifically includes the following steps:

[0136] Step 1. Put gentian into a vacuum freeze dryer with a power of 23 kW, a vacuum degree of 2 Pa, a freezing temperature of -65 °C, and a freezing duration of 12 h. Then, heat it to 2 °C and dry for 5.5 h to obtain freeze-dried gentian.

[0137] Step 2. Put the freeze-dried gentian prepared in Step 1 into an ultrafine grinder with a power of 5.8 kW, a crushing speed of 4,700 r / min, a crushing particle size of 0.3 mm, a crushing temperature of 25 °C, and a crushing duration of 33 min. After crushing, mix it with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone, and place them in a constant temperature stirrer with a power of 1.9 kW, a stirring temperature of 55 °C, a stirring speed of 80 r / min, and a stirring duration of 12 h to carry out esterification reaction modification to obtain modified gentian powder.

[0138] Step 3. Put L-menthol, lignin glycoside, pyridoxine, bradykinin, and 50% ethanol solution into a stirrer with a power of 1.7 kW, a stirring temperature of 25 °C, a stirring speed of 80 r / min, and a stirring duration of 12 min. After dissolution, put the modified gentian powder prepared in Step 2 into it, with a stirring temperature of 24 °C, a stirring speed of 80 r / min, and a stirring duration of 20 min for mixing to obtain a mood-relieving composition.

[0139] Step 4. Add a moisturizing adhesive and a nervous system regulator to the mood-relieving composition prepared in Step 3, with a stirring temperature of 24 °C, a stirring speed of 80 r / min, and a stirring duration of 23 min. After stirring evenly, a sedative maintenance agent for oral mucosal administration is obtained.

[0140] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0141] The material ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0142] Example 5: This example provides a sedative maintenance medicament for oral mucosal administration and a preparation method thereof. The sedative maintenance medicament for oral mucosal administration includes the following components in parts by weight:

[0143] 45 parts of a moisturizing adhesive, 25 parts of a 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 glycoside, 8.5 parts of pyridoxine, and 10 parts of bradykinin.

[0144] The preparation raw materials of the moisturizing adhesive include the following components in parts by weight: 26 parts of bamboo leaf polysaccharide, 24 parts of porcine 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.

[0145] The preparation raw materials of 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.

[0146] The preparation method of the moisturizing adhesive specifically includes the following steps:

[0147] S1. Put the bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water into a reaction kettle with a power of 3.2 kW, with a reaction temperature of 78 °C, a reaction speed of 80 r / min, and a reaction duration of 2.3 h, and carry out a mixed reaction to obtain a high-moisture complex;

[0148] S2. Put the methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water into a reaction kettle with a power of 3.2 kW, with a reaction temperature of 150 °C, a reaction speed of 80 r / min, and a reaction duration of 1.4 h, and carry out a methylation reaction to obtain a modified carbachol solution;

[0149] S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, with a stirring temperature of 37 °C, a stirring duration of 28 min, and a stirring speed of 500 r / min, and carry out sufficient adsorption to obtain the moisturizing adhesive.

[0150] In S1, the mass fraction of the bamboo leaf polysaccharide in the ultrapure water is 8%.

[0151] In S2, the mass fraction of the carbachol in the ultrapure water is 9%.

[0152] The preparation method of the nervous system regulator specifically includes the following steps:

[0153] L1. Put apigenin and absolute ethanol into 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 duration of 19 min, and stir and mix to obtain an apigenin solution;

[0154] 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, stir at a constant temperature of 36 °C, a constant-temperature stirring duration of 1.6 h, and a constant-temperature stirring speed of 210 r / min to obtain a complex solution;

[0155] L3. Put sodium salicylate, polyacrylate, ethyl acetate and ultrapure water into a reaction kettle with a power of 3.4 kW, react at a temperature of 83 °C, a reaction speed of 150 r / min, and a reaction duration of 2.8 h. After the reaction, keep warm at a temperature of 60 °C for 2.4 h to obtain a copolymer solution;

[0156] L4. Put lupeol, monosialotetrahexosylganglioside and 70% ethanol solution into a stirrer with a power of 1.5 kW, stir at a temperature of 58 °C, a stirring duration of 26 min, and a stirring speed of 140 r / min. After dissolution, add it to the complex solution prepared in L2, and put it into a vacuum freeze nano spray dryer with a power of 2.7 kW, a vacuum degree of -0.05 MPa, a freeze nano spray drying temperature of -40 °C, a freeze nano spray drying particle size of 100 nm, and a freeze nano spray drying duration of 2.9 h for freeze spray drying to prepare and form nanoparticles;

[0157] L5. Put the nanoparticles prepared in L4 into the copolymer solution prepared in L3, put it into an ultrasonic stirrer with a power of 1.8 kW, an ultrasonic frequency of 15 kHz, a stirring speed of 20000 r / min, a stirring temperature of 25 °C, and a stirring duration of 10 min, and disperse evenly to obtain a nervous system regulator.

[0158] In L1, the mass fraction of apigenin in absolute ethanol is 37%. In L2, the mass fraction of bovine serum albumin in ultrapure water is 4%.

[0159] In L3, the mass fraction of sodium salicylate in ultrapure water is 22%. In L4, the mass fraction of polyacrylate in ethyl acetate is 21%.

[0160] This embodiment also provides a preparation method of a sedative maintenance agent for oral mucosal administration, specifically including the following steps:

[0161] Step 1: Put gentian into a vacuum freeze dryer with a power of 28 kW, a vacuum degree of 4 Pa, a freezing temperature of -65°C, and a freezing duration of 13 h. Then, heat it up to 4°C and dry for 6.2 h to obtain freeze-dried gentian.

[0162] Step 2: Put the freeze-dried gentian prepared in Step 1 into a superfine pulverizer with a power of 6.2 kW, a pulverizing rotation speed of 5100 r / min, a pulverizing particle size of 0.3 mm, a pulverizing temperature of 27°C, and a pulverizing duration of 40 min. After pulverization, put it together with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone into a constant temperature stirrer with a power of 2.2 kW, a stirring temperature of 65°C, a stirring rotation speed of 100 r / min, and a stirring duration of 13.5 h for esterification reaction modification to obtain modified gentian powder.

[0163] Step 3: Put L-menthol, lignan glycoside, pyridoxine, bradykinin, and 50% ethanol solution into a stirrer with a power of 2.1 kW, a stirring temperature of 27°C, a stirring speed of 100 r / min, and a stirring duration of 14 min. After dissolution, put the modified gentian powder prepared in Step 2 into it, with a stirring temperature of 27°C, a stirring speed of 100 r / min, and a stirring duration of 25 min for mixing to obtain a mood-relieving composition.

[0164] Step 4: Add a moisture-retaining adhesive and a nervous system regulator to the mood-relieving composition prepared in Step 3, with a stirring temperature of 27°C, a stirring speed of 100 r / min, and a stirring duration of 28 min. Stir evenly to obtain a sedative maintenance agent for oral mucosal administration.

[0165] The volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.6.

[0166] The material-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

[0167] Experimental Example 1: Determination of the oral moisture retention and saliva secretion promoting ability of mice.

[0168] The test steps for the sedative maintenance agent for oral mucosal administration prepared in Examples 1-5 to determine the oral moisture retention and saliva secretion promoting ability of mice are as follows:

[0169] (1)Forty-two Kunming mice weighing 25 g were randomly divided into 6 groups of 7 mice each. Using a sterile swab, 0.1 g of the sedative maintenance agents prepared in Examples 1-5 for oral mucosal administration was applied to the left inner wall of the oral cavity of the mice in Experimental Examples 1-5. 0.1 g of alprazolam agent was applied to the left inner wall of the oral cavity as the CK control group. The moisture data of the inner wall of the oral cavity of each group of mice was detected using a skin moisture meter Real Bubee.

[0170] (2)On the 1st day, 10 min, 20 min, 30 min, 40 min, 50 min, and 60 min after the first application of the sedative maintenance agents prepared in the Examples for oral mucosal administration to the left inner wall of the oral cavity of the mice, the moisture data of the inner wall of the oral cavity was collected. According to the formula, the moisture content change rate (%) = (moisture content value on the left inner wall of the oral cavity - moisture content value on the right inner wall of the oral cavity) / moisture content value on the right inner wall of the oral cavity × 100%. The higher the value, the stronger the ability to moisturize and promote saliva secretion.

[0171] Experimental Example 2: Determination test of mouse blood indexes.

[0172] The steps for the determination test of the effects of the sedative maintenance agents prepared in Examples 1-5 for oral mucosal administration on mouse blood indexes are as follows:

[0173] (1)Forty-two Kunming mice weighing 25 g were randomly divided into 6 groups of 7 mice each. Using a sterile swab, 0.2 g of the sedative maintenance agents prepared in Examples 1-5 for oral mucosal administration was applied to the mice in Experimental Examples 1-5. 0.2 g of normal saline with a concentration of 0.9% was applied as the CK control group. Each group of mice was administered by applying to the inner wall of the oral cavity at 8:00 every morning, once a day, for 7 consecutive days.

[0174] (2)The mice were confined in 50 mL centrifuge tubes with holes for ventilation and padding at the tail, so that the mice could not move freely in the tubes without causing trauma. Starting from the 3rd day after applying the sedative maintenance agents prepared in Examples 1-5 for oral mucosal administration, the mice were confined for 3 h 1 h after each administration for 7 consecutive days to obtain anxious mice.

[0175] (3) Decapitate the mice to collect blood. Take 0.5 mL of blood from the posterior orbital venous plexus of the mice, let it stand for 30 min, centrifuge at 3500 r / min for 15 min to separate the serum. Use a mouse norepinephrine kit (purchased from Enzyme-linked Biology, product number: YJ11269), an acetylcholine assay kit (purchased from Enzyme-linked Biology, product number: ml093046), and a γ-aminobutyric acid assay kit (purchased from Enzyme-linked Biology, product number: ml092747) to measure the contents of norepinephrine, acetylcholine, and γ-aminobutyric acid in the mice.

[0176] Experimental Example 3: Test for the sedative effect on anxious mice.

[0177] The steps for the test on the sedative effect of the sedative maintenance agents administered through the oral mucosa prepared in Examples 1-5 on anxious model mice are as follows:

[0178] (1) Select 42 Kunming mice weighing 25 g, randomly divide them into 6 groups with 7 mice in each group. Using a sterile applicator stick, apply 0.2 g of the sedative maintenance agents administered through the oral mucosa prepared in Examples 1-5 to the mice in Experimental Examples 1-5 by smearing the inner wall of the oral cavity. Apply 0.2 g of normal saline with a concentration of 0.9% as the CK control group. Smear the inner wall of the oral cavity of each group of mice at 8:00 am every day, once a day for 7 consecutive days;

[0179] (2) Restrain the mice in a 50 mL centrifuge tube, make holes to maintain ventilation and fill padding at the tail so that the mice cannot move freely in the tube without causing trauma. Starting from the 3rd day after applying the sedative maintenance agents administered through the oral mucosa prepared in Examples 1-5, restrain the mice for 3 h 1 h after each administration every day for 7 consecutive days to obtain anxious mice;

[0180] (3) In the EPM device, two open arms and two closed arms are placed opposite each other in a cross shape. The length × width of each arm is 15 cm × 41 cm, and there is a platform in the center of the connecting arm. The maze is 30 cm above the ground, and the height of the closed arm is 12 cm. The experiment is carried out under dark conditions. At the start of the experiment, place the anxious mice into the maze from the central grid facing the closed arm, and record the activity within 5 min. The recording indicators include: the time and number of entries into the open arm, and the time and number of entries into the closed arm. Test one anxious mouse each time with the same device. After the test is completed and the anxious mouse is taken out, clean the maze and spray ethanol with a concentration of 10% to remove the odor. The evaluation indicators for the anxiety level of the experimental animals are:

[0181] Ratio of the number of entries into the open arm = (Number of entries into the open arm) / (Number of entries into the open arm + Number of entries into the closed arm) × 100%;

[0182] Entry open arm time ratio = Entry open arm time / (Entry open arm time + Entry closed arm time) × 100%.

[0183] Result analysis:

[0184] Figure 1 It is the result graph of the change rate of the moisture content of the mice described in Experimental Example 1 of the present invention. As shown in the figure, for the sedative maintenance agents administered through oral mucosa described in Examples 1-5, after being applied to the left inner wall of the oral cavity of the mice, the change rates of the moisture content of the mice are 5.37%, 6.42%, 7.56%, 8.69%, 9.46%, 9.97%, and the moisture content gradually increases. While for the control group of mice, the change rates of the moisture content of the inner wall of the oral cavity are 0.46%, 0.35%, 0.27%, 0.14%, 0.08%, 0.02%, and the moisture content gradually decreases. This shows that the sedative maintenance agent administered through 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 cavity environment, and protect the health of the oral mucosa.

[0185] Figure 2 It is the result graph of the norepinephrine content in the mice described in Experimental Example 2 of the present invention. As shown in the figure, for the sedative maintenance agents administered through oral mucosa described in Examples 1-5, after being applied to the inner wall of the oral cavity of the anxious mice, the norepinephrine content in the anxious mice is 0.64 ng / g, 0.59 ng / g, 0.54 ng / g, 0.58 ng / g, 0.56 ng / g, while the norepinephrine content in the control group of anxious mice is 1.75 ng / g; Figure 3 It is the result graph of the acetylcholine content in the mice described in Experimental Example 2 of the present invention. As shown in the figure, for the sedative maintenance agents administered through oral mucosa described in Examples 1-5, after being applied to the inner wall of the oral cavity of the anxious mice, the acetylcholine content in the anxious mice is 245 nmol / L, 249 nmol / L, 261 nmol / L, 250 nmol / L, 254 nmol / L, while the acetylcholine content in the control group of anxious mice is 155 nmol / L; Figure 4 It is the result graph of the γ-aminobutyric acid content in the mice described in Experimental Example 2 of the present invention. As shown in the figure, for the sedative maintenance agents administered through oral mucosa described in Examples 1-5, after being applied to the inner wall of the oral cavity of the anxious mice, the γ-aminobutyric acid content in the anxious mice is 19.34 mg / g, 22.79 mg / g, 25.34 mg / g, 24.54 mg / g, 23.23 mg / g, while the γ-aminobutyric acid content in the control group of anxious mice is 8.45 mg / g. This shows that the sedative maintenance agent administered through oral mucosa of the present invention can balance the excitability of the sympathetic nerve and the parasympathetic nerve, effectively play a sedative role, and promote the synthesis of the brain neurotransmitter γ-aminobutyric acid that inhibits vomiting, avoiding the occurrence of nausea and vomiting symptoms.

[0186] Figure 5 This is the result graph of the sedative effect on mice described in Experimental Example 3 of the present invention. As shown in the figure, for the sedative maintenance agents administered through oral mucosa described in Examples 1-5, when applied to the inner wall of the oral cavity of anxious mice, the ratios of the number of times the anxious mice entered the open arms were 43.73%, 45.86%, 47.42%, 46.4%, and 45.95%, and the ratios of the time the anxious mice entered the open arms were 41.35%, 43.49%, 44.57%, 43.85%, and 44.55%. For the control group of anxious mice, the ratio of the number of times they entered the open arms was 31.65%, and the ratio of the time they entered the open arms was 24.61%. This shows that the sedative maintenance agent administered through oral mucosa according to the present invention can significantly improve the occurrence of anxious behaviors.

[0187] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

[0188] The above describes the present invention and its implementation manners. Such description is not restrictive. What is shown in the drawings is only one of the implementation manners of the present invention, and the actual application is not limited thereto. Generally speaking, if those of ordinary skill in the art are inspired by it and design, without creative efforts, ways and embodiments similar to this technical solution without departing from the purpose of the present invention's creation, they shall fall within the protection scope of the present invention.

Claims

1. A sedation maintenance agent for oral mucosal administration, characterized in that, The sedative maintenance agent for oral mucosal administration specifically includes the following components in parts by weight: 30-50 parts of a moisture-retaining adhesive, 21-26 parts of a 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 lignin glycoside, 7-9 parts of pyridoxine, 6-11 parts of bradykinin, 64-76 parts of N-methylpyrrolidone; The preparation raw materials of the moisture-retaining adhesive include the following components in parts by weight: 23-27 parts of bamboo leaf polysaccharide, 20-25 parts of porcine 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, 9-10 parts of butyl acetate; The preparation raw materials of 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, 4-6 parts of monosialotetrahexosylganglioside.

2. The sedation maintenance agent for transmucosal administration according to claim 1, characterized in that, The preparation method of the moisture-retaining adhesive specifically includes the following steps: S1. Mix bamboo leaf polysaccharide, porcine skin collagen peptide, lanthanum nitrate, and ultrapure water and react to obtain a high-moisture complex; S2. Mix methyl trifluoromethanesulfonate, carbachol, ferrous sulfate, and ultrapure water, and react after mixing to obtain a modified carbachol solution; S3. Put the high-moisture complex prepared in S1 into the modified carbachol solution prepared in S2, then add chlorogenic acid and butyl acetate, and stir for sufficient adsorption to obtain a moisture-retaining adhesive.

3. The sedative maintenance agent for transmucosal 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 sedative maintenance agent for transmucosal administration according to claim 3, characterized in that, In S2, the mass fraction of the carbachol in ultrapure water is 5-10%.

5. The sedation maintenance agent for transmucosal administration according to claim 4, characterized in that, The preparation method of the nervous system regulator specifically includes the following steps: L1. Stir and dissolve apigenin in absolute ethanol to obtain an apigenin solution; L2. Stir and mix bovine serum albumin, ultrapure water, and the apigenin solution prepared in L1 to obtain a complex solution; L3. Mix sodium salicylate with polyacrylate, ethyl acetate, and ultrapure water and react to obtain a copolymer solution; L4. Stir and dissolve lupeol and monosialotetrahexosylganglioside in a 70% ethanol solution, then add them to the complex solution prepared in L2, and perform freeze spray drying to prepare and form nanoparticles; L5. Uniformly disperse the nanoparticles prepared in L4 in the copolymer solution prepared in L3 to obtain a nervous system regulator.

6. The sedative maintenance agent for transmucosal administration according to claim 5, characterized in that, In L1, the mass fraction of the apigenin in absolute ethanol is 34-38%, and in L2, the mass fraction of the bovine serum albumin in ultrapure water is 2-4%.

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

8. A preparation method of a sedation maintenance agent for transmucosal administration according to any one of claims 1-7, characterized in that, Specifically includes the following steps: Step 1: Put gentian into a vacuum freeze dryer with a vacuum degree of 2 - 5 Pa and a power of 20 - 30 kW. The freezing temperature is -65°C, and the freezing duration is 12 - 13 h. Then, raise the temperature to 2 - 4°C and dry for 5 - 6.5 h to obtain freeze-dried gentian. Step 2: Put the freeze-dried gentian prepared in Step 1 into an ultrafine pulverizer with a power of 5.5 - 6.5 kW. The pulverizing speed is 4600 - 5300 r / min, the pulverizing particle size is 0.2 - 0.4 mm, the pulverizing temperature is 25 - 28°C, and the pulverizing duration is 30 - 45 min. After pulverization, put it together with tea fruit oil, sodium hypophosphite, and N-methylpyrrolidone 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, and the stirring duration is 12 - 14 h. Stir and mix to react to obtain modified gentian powder. Step 3: Put L-menthol, lignin glycoside, pyridoxine, bradykinin, and 50% ethanol solution into a stirrer with a power of 1.6 - 2.2 kW. The stirring temperature is 23 - 28°C, the stirring speed is 80 - 100 r / min, and the stirring duration is 12 - 14 min. After dissolution, put it into the modified gentian powder prepared in Step 2. The stirring temperature is 23 - 28°C, the stirring speed is 80 - 100 r / min, and the stirring duration is 18 - 26 min for mixing to obtain a mood-soothing composition. Step 4: Add a moisturizing adhesive and a nervous system regulator to the mood-soothing composition prepared in Step 3. The stirring temperature is 23 - 28°C, the stirring speed is 80 - 100 r / min, and the stirring duration is 20 - 30 min. Stir evenly to obtain a sedative maintenance agent for oral mucosal administration. In Step 2, the volume ratio of the tea fruit oil to N-methylpyrrolidone is 1:1.

6. In Step 3, the material-liquid ratio of the L-menthol to the 50% ethanol solution is 1:1.4 g / mL.

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