CN111067921A - Preparation method of hydrogel for oropharynx - Google Patents
Preparation method of hydrogel for oropharynx Download PDFInfo
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Abstract
The invention belongs to the field of medical instruments, and particularly relates to an oropharynx hydrogel which comprises a gel matrix, citric acid, collagen, sodium hyaluronate, xylitol, silver ions, dipotassium glycyrrhizinate, benzyl alcohol, Tween-80, propylene glycol, mint, a yolk isolate and purified water, and a preparation method and application of the oropharynx hydrogel in preparation of medical supplies for relieving dental ulcer and/or sore throat.
Description
Technical Field
The invention belongs to the field of medical instruments, and particularly relates to an oropharyngeal hydrogel, a preparation method thereof and application thereof in preparing a medical article for relieving oral ulcer and/or sore throat.
Background
Oral ulcer is a common oral mucosa disease, the etiology of the oral ulcer is complex, and an ideal treatment method is not available at present. When the oral ulcer is attacked, local burning pain is obvious, and the condition of many patients is repeated frequently, so that normal diet and daily life are influenced, and the emotion of work or life is even influenced.
Swollen sore throat is the most common disease, which is often caused by cold seasons of the year, cold, tonsillitis, sinusitis, pertussis, pharyngolaryngitis, viral infection and even myocardial infarction.
The swollen sore throat requires different treatment modes according to the etiology, but generally lasts for a long time, and the life quality of a patient is seriously affected. Therefore, the development of a plurality of universal medicines or adjuvant therapeutic agents for relieving sore throat to meet huge clinical requirements has important significance.
At present, the oral gel and the oral gargle are mostly used for the adjuvant therapy of oral ulcer, such as xu Fang Hui, and the like, and discloses an oral ulcer care gel prepared from benzyl alcohol, polysorbate 60, glycerin, carbomer, citric acid, potassium hydroxide, xylitol and purified water, which is used for treating chemoradiotherapy stomatitis, oral mucositis and oral ulcer (recurrent oral ulcer or traumatic ulcer caused by operation, false teeth, orthodontics and the like) with better curative effect (xu Fang Hui, and the like, Zhongnan pharmacy, 13(5), 533-535).
Also for example, CN110215424A (published: 2019.9.10) discloses an oral ulcer gargle, which comprises a wound cleaning component, a hydrogel component, a surfactant component and a therapeutic component. Wherein the hydrogel component comprises: purified water, disodium hydrogen phosphate, saccharin sodium, carbomer homopolymer A, glycerol, citric acid, polyoxyethylene sorbitan monostearate, potassium hydroxide, benzyl alcohol, and orange essence for relieving oral ulcer.
The oral cavity gel or the gargle is used for the auxiliary treatment of the oral ulcer, the function of relieving the sore throat is not mentioned, and the oral cavity hydrogel provided by the invention can relieve the oral ulcer and also can remarkably relieve the sore throat.
Disclosure of Invention
The invention aims to provide an oropharyngeal hydrogel, a preparation method thereof and application thereof in preparing medical supplies for relieving oral ulcer and sore throat.
The invention provides a hydrogel for oropharynx, which comprises the following components: gel matrix, citric acid, collagen, sodium hyaluronate, xylitol, silver ions, dipotassium glycyrrhizinate, benzyl alcohol, tween-80, propylene glycol, menthol, yolk isolate and purified water.
The citric acid can also be trisodium citrate, sodium dihydrogen phosphate and disodium hydrogen phosphate; the collagen can be fish collagen or other animal collagen; the sodium hyaluronate may also be hyaluronic acid; the xylitol can be sorbitol, mannitol; the dipotassium glycyrrhizinate can be diammonium glycyrrhizinate, monoammonium glycyrrhizinate, trisodium glycyrrhizinate, disodium glycyrrhizinate, monopotassium glycyrrhizinate, and glycyrrhizic acid; the tween 80 can be CO-40, tween 20 or tween 60; the propylene glycol may also be 1,3 butanediol; the menthol can also be mint essence.
The hydrogel of the invention is a water-like gel, has strong fluidity, and can be prepared into a spray to be sprayed in the oral cavity.
Further, the gel matrix of the oropharyngeal gel is carbomer and a component A, wherein the component A is selected from triethanolamine, chitosan, hydroxyethyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose, and is preferably triethanolamine.
Furthermore, each 100ml of hydrogel contains 0.16-0.3 g of gel matrix, 0.02-0.05 g of citric acid, 0.03-0.06 g of collagen, 0.2-0.4 g of sodium hyaluronate, 2.5-3.5 g of xylitol, 0.02-0.06 g of dipotassium glycyrrhizinate, 0.2-0.5 g of benzyl alcohol, 0.78-1.5 g of tween-800.5, 1-2 g of propylene glycol, 0.01-0.03 g of menthol, 0.05-0.15 g of yolk isolate, 5-100ppm of silver ions and the balance of purified water.
Furthermore, per 100ml of hydrogel, 0.08-0.15 g of carbomer, 0.08-0.15 g of triethanolamine, 0.02-0.05 g of citric acid, 0.03-0.06 g of collagen, 0.2-0.4 g of sodium hyaluronate, 2.5-3.5 g of xylitol, 0.02-0.06 g of dipotassium glycyrrhizinate, 0.2-0.5 g of benzyl alcohol, 0.78-1.5 g of tween-800.5, 1-2 g of propylene glycol, 0.01-0.03 g of menthol, 0.05-0.15 g of yolk isolate, 5-100ppm of silver ions and the balance of purified water.
More preferably, per 100ml of hydrogel, 0.12% of carbomer, 0.12% of triethanolamine, 0.04% of citric acid, 0.05% of collagen, 0.3% of sodium hyaluronate, 3% of xylitol, 0.05% of dipotassium glycyrrhizinate, 0.4% of benzyl alcohol, 1.5% of tween-801, 1.5% of propylene glycol, 0.02% of mint, 0.10% of yolk isolate, 5-100ppm of silver ions and the balance of purified water.
Further, the carbomer types are: carbomer-980.
The oropharynx hydrogel is prepared by mixing the components, and carbomer needs to be prepared into a pre-solution firstly.
Further, a hydrogel for oropharynx is prepared by the following steps:
(1) adding carbomer into a mixing tank, adding purified water, and swelling completely; as a pre-solution 1;
(2) adding sodium hyaluronate, collagen, dipotassium glycyrrhizinate, yolk isolate, xylitol, silver ions and citric acid into purified water, and stirring until the sodium hyaluronate, the collagen, the dipotassium glycyrrhizinate, the yolk isolate, the xylitol, the silver ions and the citric acid are completely dissolved to obtain a pre-solution 2;
(3) mixing tween-80 and propylene glycol, stirring, adding Mentholum, and stirring to dissolve completely to obtain pre-solution 3;
(4) sequentially adding the pre-solutions 2 and 3, benzyl alcohol and triethanolamine into the pre-solution 1, stirring, dissolving and uniformly mixing;
(5) adding the rest purified water, and stirring for 10min to obtain a uniform solution.
The oropharynx hydrogel disclosed by the invention can be used for preparing a medicine for relieving oral ulcer and/or sore throat.
Further, sore throat is a sore throat caused by upper respiratory tract infection.
The oropharyngeal hydrogel is prepared from low-toxicity materials such as carbomer and hyaluronic acid and is used for ensuring the use safety, experimental results also show that the oropharyngeal hydrogel is good in safety and free of irritation to mucous membranes, in an experiment on the effect of oral mucosal ulcer, the oropharyngeal hydrogel can be seen to have a good promoting effect on the healing of the wound surface of the oral ulcer through tissue slices, and the levels of TNF- α, IL-1 β and IL-6 at the ulcer part can be slightly reduced from the detection result of inflammatory factors at the ulcer part, so that the effects can play a good auxiliary role in the treatment of the oral ulcer.
The oropharynx hydrogel can effectively relieve sore throat caused by upper respiratory tract infection, and has better effect than a control group. The adverse reaction is extremely small, and the medicine can be recovered after being stopped.
By using the product of the invention, the capillary vessel of the using part is contracted, the sensitivity of the skin nerve endings is reduced, and the purpose of cold compress can be achieved; is helpful for relieving oral ulcer, and swelling and pain, and dry itching of oropharynx caused by common cold and excessive internal heat. Can also relieve symptoms of xerostomia of patients after operation and radiotherapy and chemotherapy.
Unless otherwise indicated, the terms used in the specification and claims have the following meanings.
The term "medical article" as used herein refers to a generic term for articles used for treating wounds or treating diseases. Including but not limited to pharmaceuticals, medical devices, medical dressings, and medical aids.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Drawings
Fig. 1 shows the change of the body weight of each group of mice with the maximum amount of the product (n is 10) in one day;
figure 2 maximum tolerance per day the body weight of each group of mice was varied (n-10);
FIG. 3 mucous membrane pathological section view of oral mucous membrane tissue irritation experiment (10 ×)
A. Oropharyngeal hydrogel group; B. blank control group;
FIG. 4 pathological section of rat oral mucosa (HE,4 ×) (n ═ 6)
A. Oropharyngeal hydrogel group; B. a iodoglycerol control group; C. blank control group; D. and (4) a positive control group.
Detailed Description
The present invention will be further described below by way of specific examples and test results.
EXAMPLE 1 preparation of oropharyngeal hydrogel I
TABLE 1 oropharyngeal hydrogel I dosage
The preparation method comprises the following specific preparation steps (according to the feeding amount in the table 1):
(1) carbomer was weighed and thoroughly swollen with an appropriate amount of purified water as pre-solution 1.
(2) Adding 500mL of purified water into sodium hyaluronate, collagen, dipotassium glycyrrhizinate, yolk isolate, xylitol, silver ions and citric acid, and stirring until the sodium hyaluronate, the collagen, the dipotassium glycyrrhizinate, the yolk isolate, the xylitol, the silver ions and the citric acid are completely dissolved to obtain a pre-solution 2;
(3) weighing Tween-80 and propylene glycol, mixing and stirring uniformly, adding menthol in a formula amount, and stirring until the menthol is completely dissolved to obtain a pre-solution 3;
(4) then adding the pre-solutions 2 and 3, benzyl alcohol and triethanolamine into the pre-solution 1 in sequence, stirring, dissolving and uniformly mixing;
(5) adding the rest purified water, diluting to 1000mL, and stirring for 10min to make the solution uniform to obtain the oropharyngeal hydrogel.
EXAMPLE 2 preparation of hydrogel II for oropharynx
TABLE 2 dosage of hydrogel II for oropharynx
Hydrogel ii for oropharynx was prepared according to the preparation method of example 1 with the charge amounts shown in table 2.
EXAMPLE 3 preparation of oropharyngeal hydrogel III
TABLE 3 dosage of oropharyngeal hydrogel III
An oropharyngeal hydrogel iii was prepared according to the preparation method of example 1 with the charge amounts shown in table 3.
The prepared oropharyngeal hydrogel was tested for safety and efficacy by the following tests.
Test example 1 acute toxicity test of oropharyngeal gel and test for treating oral ulcer in rat
1 Material
1.1 animal SD rat, clean grade, male and female halves, weight 200-: SCXK (Shanghai) 2017-. ICR mice, clean grade, female, body weight 24-33g, provided by shanghai slek laboratory animals llc, laboratory animal license number: SCXK (Shanghai) 2016-0002.
1.2 reagent oropharynx hydrogel I (batch No.: CCG 190601); ELISA kit (enzyme-linked biology, Inc., batch number: LOT 20190506); hematoxylin (Jianglai biological Co., Ltd., batch No. 20180301); paraformaldehyde (Hubei xing Galaxy chemical Co., Ltd., lot number: L1521018).
1.3 Instrument high speed tissue homogenizer (Qimo electronics technologies, Inc.); nikon YS100 type biomicroscope (Nikon corporation, japan); model LS-2065 paraffin slicer (Hebei Huiyi science and technology Co., Ltd.); JY-BMC type biological tissue freezing embedding machine (Hubei jin source medical science and technology Co., Ltd.).
2 method
2.1 test drug oropharyngeal hydrogels: oropharyngeal hydrogel I prepared in example 1.
2.2 acute toxicity evaluation
2.2.1 mouse LD50Measurement 20 ICR mice, half male and half female, were randomly divided into 2 groups of 10 mice each. Is divided into an oropharyngeal hydrogel group and a normal saline group. The maximum dose of the product for intragastric administration of the mouse is 0.3mL/10g, and the maximum dose is not more than 1.0 mL/mouse, and the oropharyngeal hydrogel for intragastric administration has the concentration which is 100 times of that of the clinical preparation. The mice were scored for changes in body weight, appearance, behavior, diet, secretions, and excretions after being vaccinated.
2.2.2 measurement of maximum daily tolerability (MTD) in mice LD50 could not be determined even when oropharyngeal hydrogel was administered to animals at the maximum permissible concentration and maximum permissible volume, and in order to further understand the toxicity of the preparation, a measurement of maximum daily tolerability (MTD) was carried out. 10 ICR mice are taken, and the variety is administrated by gavage according to the dosage of oropharyngeal hydrogel of 0.3mL/10g, and the variety is administrated 1 time at 6-hour intervals. The strain was administered 3 times and continuously observed for 7 days, and the appearance (change in body weight, skin and hair, eye and mucous membrane), behavior, diet, secretion, excretion, poisoning and death of the mice administered with the strain were recorded, and the saline solution group was used as a control in the above procedure.
2.3 rat oral mucosa irritation test
2.3.1 oral mucosa of rat 18 SD rats with body weight of 200-210g and half of male and female were selected from the rat species and randomly divided into 2 groups, i.e. oropharyngeal hydrogel group and blank control group. The oropharyngeal hydrogel group was sprayed into the oral cavity of the rat in a fixed amount, repeated every 1h for 4 consecutive times, and the blank group was administered 0.9% physiological saline according to the same method as above. After the product is planted for 7 days, the buccal mucosa and surrounding tissues of the product are sampled the next day of the last time, and the stimulation of the oropharyngeal hydrogel to the oral mucosa is evaluated by the examination of pathological histological sections.
2.3.2 HE staining of the mucous membrane of the lower buccal cavity of the rat and the surrounding tissues after the rat was sacrificed, pathological tissue sections were taken of the mucous membrane of the lower buccal cavity of the rat and the surrounding tissues. Collecting buccal mucosa and peripheral tissue of the strain, wherein the tissue block size is no more than 1.5cm × 1.5cm × 0.5 cm. After preliminary trimming, putting the cut pieces into 4% paraformaldehyde as soon as possible for fixation, and placing the cut pieces at normal temperature for 24-48 hours. Dehydrating with 70%, 80% and 90% ethanol solution, making tissue completely transparent with xylene, soaking in wax, embedding, slicing, HE staining, sealing, and observing under microscope.
2.3.3 histological observational evaluation the evaluation was made in terms of the degree of oral mucosal irritation of the oropharyngeal hydrogel. Grading pathological reactions: 0-4 points, grade is not available; 5-8 points, and the grade is mild; 9-11 points, medium grade; grade severity is 12-16 points. Mucosal tissue morphological changes were observed under light microscopy and scored as in table 4.
TABLE 4 oral mucosal histopathological response scoring criteria
2.4 Effect test on rat canker sore
2.4.1 establishing a rat oral ulcer model, fasting is carried out 24 hours before model building, water is normally drunk, after 20% of urethane is used for intraperitoneal injection and anesthesia on the next day, filter paper sheets with equal areas are dipped in 40% of glacial acetic acid and placed on lower buccal mucosa of the rat for half an hour, and ulcer can appear on the 2 nd day of the experiment.
2.4.2 test grouping and for this breed, 48 SD rats with weight of 200-210g and half of male and female were selected and randomly divided into 4 groups of 12 rats each, namely: (1) iodoglycerol control group: oral ulcer model rats were given iodoglycerol; (2) the product is prepared into the following groups: oral ulcer model rats were given oropharyngeal hydrogels; (3) blank control group: normal rats are given 0.9% normal saline in the buccal cavity; (4) positive control group: the canker sore model was not treated.
2.4.3 Observation indicators and methods
On the 2 nd day (after 24 h) of model making, the rats successfully molded are fed according to the group, 0.1mL of oropharyngeal hydrogel is fed to the lower cheek of the oral cavity of the rat, so that the liquid of the product is fully contacted with the ulcer surface and is repeated for 4 times continuously every 2h, 5d, the iodoglycerol control group and the blank control group are continuously operated according to the same method of the steps, the animals are killed after 1h of the last time of the product variety, and the cheeks and surrounding tissues of the product are respectively taken for HE staining observation (the method is as under the item of 2.2.2) and detection of inflammatory factors (TNF- α, IL-1 β and IL-6).
Sampling oral ulcer parts of oral cavity lower cheeks of rats in each group, keeping the area and weight of tissue blocks consistent during sampling, cleaning the tissue blocks in precooled PBS (0.02mol/L, pH 7.0-7.2) to remove blood for later use, adding the tissue blocks into the precooled PBS (the mass volume ratio of the tissue to the PBS is 1:5), fully grinding the tissue blocks by a homogenizer, centrifuging the prepared homogenate for 5 minutes at 5000 Xg, and taking supernatant to detect the contents of TNF- α, IL-1 β and IL-6 in the oral cavity lower cheek tissues of the rats by an ELISA kit.
3 results
3.1 acute toxicity test evaluation
3.1.1 mouse LD50Measurement results
After each group of mice is given to the strain, the mice are temporarily laid still, and the mice recover to be normal after about 1 hour without death. When the mice in this product group and the control group were given, the color of the feces and urine was normal, and the hair color was glossy. Is connected withAfter 7 days, the body weights of the mice were weighed at the same time every day after the administration of the strain. Results (FIG. 1) the data show that the body weight of mice in each dose group is not statistically different (P) from that of the blank control group>0.05). After the strain is given, mice in each group of 14d have no death and abnormal reaction. The mice are sacrificed and after dissection, the volumes, colors and textures of the main organs of the mice, such as the heart, the liver, the spleen, the lung, the kidney, the stomach, the pancreas, the large intestine, the small intestine and the like, are not obviously changed, so that LD (laser diode) cannot be measured50。
3.1.2 MTD assay results in mice
After the strain is given, all the animals have no abnormality, except for transient discomfort and reduced activity after the intragastric administration of the mice on the 1 st day, the animals have no animal poisoning and death. The results (FIG. 2) show that the mice given this group had no statistical difference in body weight compared to the control group (P > 0.05). After the strain is given, rats in each group of 7d have no death and no abnormal reaction. Sacrifice, and no obvious change in the volume, color and texture of the main organs such as heart, liver, spleen, lung, kidney, stomach, pancreas, large intestine, small intestine and the like is observed. The concentration of the preparation given to mice in the experiment is 100 times of that of the finished product, and the daily cumulative dose is 144 times of the daily dose planned to be recommended by clinical adults. The clinical application safety of the oropharyngeal hydrogel is higher.
3.2 oral mucosal tissue irritation test results
When the oropharyngeal hydrogel is applied to the lower cheek of the oral cavity of a rat, no general condition abnormality is found, and when the oropharyngeal hydrogel group HE stained tissue section is observed under a microscope, the tissue epithelial cell tissue layer is clear, the mucosal epithelium is complete, inflammatory cell infiltration and edema phenomena are not generated, the tissue thickness is 1.2-1.3 mm, and the vascular congestion state is not seen in the lamina propria. There was no significant difference compared to the saline control group (see fig. 3).
The oropharyngeal hydrogel group and the blank control group were observed under a microscope, and the pathological reaction of the oral mucosa tissues of the rats in each group was scored and graded according to the evaluation standard of the pathological reaction of the oral mucosa tissues (see table 5).
The oral mucosa irritation test is generally used for evaluating irritation of the product on oral mucosa tissue after contacting with the oral tissue. As seen from the results of observation by a light mirror after tissue section, the stimulation reaction result of the oropharyngeal hydrogel to the oral mucosa is negative, and the oropharyngeal hydrogel can be considered to have no stimulation to the oral mucosa.
TABLE 5 oral mucosal histopathological response Scoring and grading
3.3 Effect on rat canker sore test results
3.3.1 pathological tissue section results
The conditions of the various groups after being fed with the variety are observed under a mirror (see figure 4), the positive control group has obvious edema, the mucosal epithelium with the tissue thickness of 2-2.2 mm falls off, the cell tissue layers are fuzzy, and the arrangement is irregular. The iodine-glycerol control group is improved in edema phenomenon, the epithelial cell tissue level is clear, the mucosal epithelium is complete, but 2-3 inflammatory cells can be seen. The oropharyngeal hydrogel group improves edema after being given to the strain, the tissue thickness is 1.2-1.3 mm, the thickness is not obviously different from that of the iodoglycerol group, the tissue level of epithelial cells is clear, the mucosa epithelium is complete, and 1-2 inflammatory cells appear. The tissue epithelial cell tissue of the blank control group is clear in layer, and 0-1 inflammatory cell appears and is complete in mucosal epithelium.
3.3.2 comparison of TNF- α, IL-1 β, IL-6 levels in rat buccal tissue
The experiment uses TNF- α, IL-6 and IL-1 β as detection indexes to observe the influence of the oropharyngeal hydrogel on the rat oral inflammatory response, and the result shows that the oral cavity local TNF- α, IL-1 β and IL-6 levels of the rat oral ulcer are obviously increased, the levels of TNF- α, IL-1 β and IL-6 can be reduced to a certain degree after the oropharyngeal hydrogel is administered, and the reduction effect of the oropharyngeal hydrogel on the IL-1 β level is better than that of the iodoglycerol group (see Table 6).
TABLE 6 comparison of TNF- α, IL-1 β, IL-6 content in lower buccal tissue of rats in each group
4 conclusion
The oropharyngeal hydrogel of the invention belongs to medical dressing, only protects the wound surface of an ulcer part, reduces the probability of aggravation of infection, and contains components such as menthol and the like in the formula, so that the capillary vessels of an affected part are contracted, the sensitivity of nerve endings of the affected part is reduced, and the purposes of cold compress, pain relief and pain relief of a patient are achieved.
The oropharyngeal hydrogel is prepared from low-toxicity materials such as carbomer and hyaluronic acid and has the advantages of good safety and no irritation to mucous membrane, the oropharyngeal hydrogel can be well promoted to heal the wound surface of the oral ulcer through tissue slicing in an experiment on the effect of the oral mucosal ulcer, the levels of TNF- α, IL-1 β and IL-6 at the ulcer part can be slightly reduced from the detection result of inflammatory factors at the ulcer part, and the effects can play a good auxiliary role in treating the oral ulcer.
Test example 2 evaluation of clinical efficacy in relieving sore throat caused by upper respiratory infection
The oropharyngeal hydrogel developed in example 1 is used to relieve sore throat caused by upper respiratory tract infection, and a significant curative effect is obtained, specifically as follows.
1 data and method
1.1 diagnostic criteria
The Western medicine diagnosis standard refers to the technical scheme that the old tertiary objective beads are compiled in practical science (10 th edition) for upper respiratory tract infection, ① has a history of influenza contact, ② is mainly based on local symptoms, all symptoms can be obvious or not, the local symptoms comprise sneezing, nasal obstruction, watery nasal discharge, cough, sore throat, hoarseness and lacrimation in some cases, the general symptoms comprise aversion to cold, fever, general discomfort, headache, dizziness, soreness and pain of the waist and the back of limbs, and ③ is generally normal or higher in leucocyte count (WBC).
According to the diagnostic criteria of wind-heat syndrome in the Chinese medicinal product, new product species clinical research guidelines (trial implementation), the main symptoms are: marked fever, slight aversion to wind, obstructed sweating, dry throat, or red, swollen and painful tonsillitis in throat, nasal obstruction, yellow and turbid nasal discharge, and superficial and rapid pulse. The secondary symptoms are as follows: distending pain in the head, cough, sticky or yellow sputum, thirst with desire for water, thin, white and yellowish tongue and red tiptoe [2], with dry throat or red swelling and pain of the tonsillitis in the throat as the main symptoms.
1.2 case data
In the experiment, 170 patients suffering from sore throat caused by wind-heat type common cold are selected from the affiliated people hospital of the Fujian traditional Chinese medicine university, the affiliated second people hospital outpatient service and the hospitalization for relieving the upper respiratory infection in 10 months to 7 months in 2019 in 2018. According to the random control principle, 85 cases of oropharyngeal hydrogel I (prepared by the method of the invention in the example 1) treatment groups (A) and oral ulcer gargle (Zhejiang instrument standard 20182630015) control groups (B) are respectively prepared.
Group a had 38 men and 47 women; the age is 13-65 years, the average (34.82 + -10.45) years, the course of disease is 12-24 hours, and the average (29.12 + -7.56) hours.
39 men and 46 women in group B, aged 12-63 years, and the average (33.96 +/-10.23) years; the course of the disease is 14-35 h, and the average is (28.46 +/-8.35) h.
① meets diagnosis criteria of upper respiratory tract infection cold wind heat syndrome induced pharynx dryness or sore throat dialectical criteria, wherein the diagnosis criteria include higher white blood cell count and higher neutrophil count ratio in cell classification, primarily judged as bacterial infectors, ② disease course is less than or equal to 36h, ③ years of 12-65 years of age, male and female are randomized, ④ patients agree with the conditions and sign informed consent, exclusion criteria include ① pregnant or lactating women, ② with serious primary diseases of heart, lung, liver, kidney, hematopoietic system and the like, mental conscious disturbance patients, ③ pneumonia, acute and chronic bronchitis, suppurative tonsillitis, lung abscess, bronchial asthma, bronchiectasis and other secondary infectors, ④ WBC > 4X 109 and lymphocyte ratio > 40%, suspected virus infectors, antibiotics or antipyretic specimen varieties used 12h before oral administration are selected as virus infectors, ⑥ allergic constitution or allergic patients to treatment and contrast specimen varieties, ② has history, alcohol history, 580 is suspected to be virus infectors, and other clinical trial subjects have reduced abuse possibility or other factors to be selected as normal study subjects according to the clinical trial history of the medicine, and other clinical trial results are selected as 38725.
1.3 cases of exfoliation and handling
The cases of abscission: poor subject compliance, severe adverse events, self-withdrawal, etc. are all cases of abscission. The statistical analysis is combined with the actual situation for processing; if the adverse reaction occurs in the product, the statistics of the adverse reaction should be taken into account.
Treatment of cases of exfoliation: when the subject falls off, the subject should be asked for a reason, and the time for taking the seed for the last 1 time is recorded, thereby completing the completed observation item. The test requires that the number of shed cases in each group does not exceed 20% of the total number of test cases.
1.4 rejection and discontinuation criteria for cases
① the patients who are not eligible for selection or eligible for exclusion after selection, ② the patients who have not been taken for 1 time after random grouping for treatment of the variety, ③ the patients who have no test record, ④ the patients who have not been taken for any other prohibited use and have affected the judgment of the curative effect of the treatment of the variety, ⑤ the patients quit within 1d after entering the test, do not finish the specified observation period and do not count as the test cases, if the patients quit after entering the test 1d, the patients who have failed to continue the test due to the allergy or adverse reaction of the variety count as the observation cases and count as the adverse reaction cases for evaluation, and ⑥ the lost visitors who have not described the reason for adverse reaction.
1.5 methods of treatment
Both groups of patients were given general routine care including full rest, light diet, rational nutrition, etc. Measuring body temperature (ohm dragon electronic thermometer) for 1 time in an observation period until thermal degradation; the throat and upper respiratory tract were observed 1 time every 6h until the sore throat disappeared.
Group a administration of the inventive developed oropharyngeal hydrogel I: the composition can be administered 3-5 times daily, and at least 6 times (0.125 g/time) per time, with the dosage being increased according to symptoms.
Group B oral ulcer mouthwashes: zhejiang et al (Zhenzhou Ji) 20182630015, Hangzhou Ji (Hangzhou Ji) is a gargle preparation.
Two groups of treatment courses are 5-7 days, and 1 treatment course is observed.
1.5.1 observing the item, observing and recording the duration and the degree of fever of all patients, and detecting the body temperature for 1 time within 1 hour; observing the red swelling and pain of throat and the tonsil inflammation degree and duration of the patient, and recording for 1 time every 6 h; observing the upper respiratory tract infection and other symptom changes of the patient, such as cough, running nose, pharyngalgia, thirst and the like; and (4) detecting the routine of blood, urine and stool and the functions of liver and kidney.
1.5.2 the symptom judgment standard is according to the grading evaluation standard of cold symptoms in the grading quantitative standard of cold symptoms in the clinical research guiding principles (trial) of Chinese New product.
1.5.3 Standard ① for disease curative effect is to use this seed to cure the disease with normal internal body temperature for 48h, no recurrence, ② effective, that is, use this seed to cure the disease with normal internal body temperature for 48h, total integral of sign of symptom reduced by >2/3, ③ effective, that is, use this seed to cure the disease with normal internal body temperature for 72h, but recurrence, total integral of other symptoms.
1.6 statistical methods
SPSS 16.0 statistical software is used for data analysis, the measurement data is expressed by mean plus or minus standard deviation (x plus or minus s), ① counting data, the composition ratio of two groups of pharyngalgia (or pharyngalgia alleviation) with different relief degrees and the curative effect comparison of disease symptoms after the product is planted are carried out by using the column X row X2 test, ② measurement data, the comparison of two groups of body temperatures with different time points is carried out, the variance analysis by repeated measurement design is carried out, and the difference P <0.05 is used for t test, thus having statistical significance.
2 results
2.1 comparison of body temperature in two groups of patients over 72h
The comparison results of the average body temperatures of two groups of patients within 24h, 24-48 h, 48-72 h and 72-120 h show that the body temperature of the group A patients is obviously reduced. The comparison of body temperatures at two different time points showed that the difference was statistically significant (P <0.05) by t-test. See table 7.
TABLE 7 comparison of body temperature in two groups of patients at 72h
2.2 comparison of the relief of swollen sore throat symptoms in 72h for two groups of patients
According to a grading quantitative evaluation table of cold symptoms, grading pharyngalgia symptoms: dry throat and slight pain are mild (1 point); sore throat with red and swollen as middle (2 points); sore throat, hoarseness (3 points); disappearance of symptoms was scored as 0 point. Compared with the results of relieving the symptoms of the angina of two groups of patients within 24 hours, 24-48 hours, 48-72 hours and 72-120 hours, the results show that the group A is obviously superior to the group B. Comparing the frequency (composition ratio) of group A and group B, the difference has statistical significance (X2 is more than or equal to 0.05, P is less than 0.05) by X2 test. See table 8.
TABLE 8 comparison of the relief of sore throat symptoms in 72h for two groups of patients
2.3 comparison of therapeutic efficacy of disease symptoms
The clinical effect comparison of the two groups after the product is planted shows that the total effective rate of the group A is 98.82%, and the total effective rate of the group B is 80.00%. The treatment effect of the group A and the group B is compared, and the difference has statistical significance by the X2 test (X2 is 10.729, P is less than 0.05).
See table 9.
TABLE 9 comparison of the efficacy of the two groups of patients after treatment
2.4 adverse reactions
During the treatment period, no adverse reaction of the product obviously influencing the treatment occurs in the two groups. The adverse reaction rate of the group A is lower than that of the group B, and the difference is not statistically significant (P is 0.226) through statistical analysis. Adverse reactions in group a were mainly mild, transient leukopenia and mild elevation of glutamate pyruvate transaminase; adverse reactions in group B were mainly: gastrointestinal reaction (slight abdominal pain, diarrhea, nausea, vomiting, etc.), liver function disorder, elevation of glutamate pyruvate transaminase and glutamate oxaloacetate transaminase, peripheral blood cell decrease, etc. After treatment, the two groups of patients have blood routine and liver and kidney functions, and the difference of each index is not statistically significant compared with that before treatment.
The research result shows that the throat swelling and pain relieving rate of the research group after treatment is obviously higher than that of the control group (P is less than 0.05); the body temperature difference of the patients in the two groups before treatment is not obvious (P is more than 0.05), the body temperature difference of the groups at every two moments is not obvious (P is more than 0.05) except the control group after treatment for 24 hours, and the body temperature of the study group is obviously lower than that of the control group (P is less than 0.05); the total effective rate of the study group is obviously higher than that of the control group (P is less than 0.05). Consistent with the above study.
The oropharynx hydrogel can effectively relieve sore throat caused by upper respiratory tract infection, and has better effect than a control group. The adverse reaction is extremely small, and the medicine can be recovered after being stopped.
In conclusion, the oropharynx hydrogel disclosed by the invention is good in safety, can effectively relieve oral ulcer, can slightly reduce the levels of inflammatory factors TNF- α, IL-1 β and IL-6 at ulcer parts, has a good auxiliary effect on treatment of oral ulcer, particularly can effectively relieve sore throat caused by upper respiratory tract infection, and has a very good clinical application prospect.
Claims (10)
1. An oropharyngeal hydrogel, characterized in that: comprises the following components: gel matrix, citric acid, collagen, sodium hyaluronate, xylitol, silver ions, dipotassium glycyrrhizinate, benzyl alcohol, tween-80, propylene glycol, menthol, yolk isolate and purified water.
2. The oropharyngeal hydrogel of claim 1, characterized in that: each 100ml of the hydrogel comprises 0.16-0.3 g of gel matrix, 0.02-0.05 g of citric acid, 0.03-0.06 g of collagen, 0.2-0.4 g of sodium hyaluronate, 2.5-3.5 g of xylitol, 0.02-0.06 g of dipotassium glycyrrhizinate, 0.2-0.5 g of benzyl alcohol, 1-1.5 g of tween-800.5, 1-2 g of propylene glycol, 0.01-0.03 g of menthol, 0.05-0.15 g of yolk isolate, 5-100ppm of silver ions and the balance of purified water.
3. The oropharyngeal hydrogel of claim 1, characterized in that: the gel matrix is carbomer and a component A; the component A is one or more selected from triethanolamine, chitosan, hydroxyethyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose, preferably, the component A is triethanolamine.
4. The oropharyngeal hydrogel according to any one of claims 1 to 3, characterized in that: each 100ml of the hydrogel contains 0.08-0.15 g of carbomer, 0.08-0.15 g of triethanolamine, 0.02-0.05 g of citric acid, 0.03-0.06 g of collagen, 0.2-0.4 g of sodium hyaluronate, 2.5-3.5 g of xylitol, 0.02-0.06 g of dipotassium glycyrrhizinate, 0.2-0.5 g of benzyl alcohol, 0-1.5 g of tween-800.5, 1-2 g of propylene glycol, 0.01-0.03 g of menthol, 0.05-0.15 g of yolk isolate, 5-100ppm of silver ions and the balance of purified water.
5. The oropharyngeal hydrogel of claim 4, characterized in that: each 100ml of the hydrogel contains 0.12g of carbomer, 0.12g of triethanolamine, 0.04g of citric acid, 0.05g of collagen, 0.3g of sodium hyaluronate, 3g of xylitol, 0.05g of dipotassium glycyrrhizinate, 0.4g of benzyl alcohol, 801 g of tween-801, 1.5g of propylene glycol, 0.02g of menthol and 0.10g of yolk isolate, wherein the dosage of silver ions is 5-100ppm, and the balance of purified water.
6. The oropharyngeal hydrogel according to any one of claims 1 to 5, characterized in that: the carbomer is prepared from the following types: carbomer-980.
7. A method for preparing a hydrogel for oropharynx according to any one of claims 1 to 6, characterized in that: prepared by mixing the components.
8. The method of claim 7, wherein: the hydrogel for oropharynx is prepared by the following steps:
(1) adding carbomer into a mixing tank, adding purified water, and swelling completely; as a pre-solution 1;
(2) adding sodium hyaluronate, collagen, dipotassium glycyrrhizinate, yolk isolate, xylitol, silver ions and citric acid into purified water, and stirring until the sodium hyaluronate, the collagen, the dipotassium glycyrrhizinate, the yolk isolate, the xylitol, the silver ions and the citric acid are completely dissolved to obtain a pre-solution 2;
(3) mixing tween-80 and propylene glycol, stirring, adding Mentholum, and stirring to dissolve completely to obtain pre-solution 3;
(4) sequentially adding the pre-solutions 2 and 3, benzyl alcohol and triethanolamine into the pre-solution 1, stirring, dissolving and uniformly mixing;
(5) adding the rest purified water, and stirring for 10min to obtain a uniform solution.
9. Use of the hydrogel for oropharynx according to any one of claims 1 to 6 for preparing a medical product for relieving oral ulcer and/or sore throat.
10. Use according to claim 9, characterized in that: the swollen sore throat is swollen sore throat caused by upper respiratory tract infection.
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