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CN115040666B - Medical ultrasonic coupling agent and preparation method thereof - Google Patents

Medical ultrasonic coupling agent and preparation method thereof Download PDF

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CN115040666B
CN115040666B CN202111190846.2A CN202111190846A CN115040666B CN 115040666 B CN115040666 B CN 115040666B CN 202111190846 A CN202111190846 A CN 202111190846A CN 115040666 B CN115040666 B CN 115040666B
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gelatin
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chitosan
couplant
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CN115040666A (en
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倪卓
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Tuoteng Huabao (Suzhou) Biotechnology Co.,Ltd.
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Shenzhen Huabao Biomaterial Technology Co ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
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    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5052Proteins, e.g. albumin
    • A61K9/5057Gelatin
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Abstract

The invention provides a medical ultrasonic coupling agent and a preparation method thereof, wherein the medical ultrasonic coupling agent contains microcapsules with a capsule core substance serving as a sterilizing disinfectant, and the capsule wall structure of each microcapsule has chemical water-soluble gel characteristics, so that the requirements of ultrasonic medicine on sound velocity, sound attenuation and sound impedance characteristics of the coupling agent can be met.

Description

Medical ultrasonic coupling agent and preparation method thereof
Technical Field
The invention relates to the technical field of medical treatment, in particular to a medical ultrasonic coupling agent and a preparation method thereof.
Background
In the conventional B ultrasonic examination or ultrasonic treatment process, because the antagonism phase difference between the ultrasonic probe and the skin is larger due to the existence of air, the ultrasonic waves emitted by the ultrasonic probe cannot pass through the skin and enter the human body, so that the medical ultrasonic couplant is generated, and the medical ultrasonic couplant is smeared between the ultrasonic probe and the skin surface, so that the effect of isolating the air can be achieved. The medical ultrasonic couplant is a water-based polymer gel material which is filled between an ultrasonic probe and human skin, and establishes a coupling effect between the probe and the human skin so that ultrasonic waves can smoothly spread into the human body to obtain reliable detection diagnosis images or achieve the aim of effective treatment, and is a medium which needs to be used in the ultrasonic diagnosis and treatment process. The ultrasonic couplant plays a very important role in ultrasonic diagnosis and treatment, plays a role of a lubricant besides the role of a medium, and is not only focused on the acoustic characteristics, but also effective and safe in clinical application. Wherein, the effectiveness mainly refers to sound transmission effect, and the safety mainly refers to influence on human tissues and prevention of cross infection.
The traditional ultrasonic couplant has no disinfection and bacteriostasis effects, so that a pathogenic bacteria transmission channel is formed between the ultrasonic probe and human skin, and the problem of multiple bacteria infection in the ultrasonic diagnosis and treatment process is caused. Therefore, the preparation of the disinfection type medical ultrasonic couplant replaces the traditional medical ultrasonic couplant to be an intervention measure widely popularized at present. Medical ultrasonic couplant used in the market at present is mainly prepared by using hydroxyethyl cellulose or carbomer as a thickening agent, using propylene glycol, glycerol or polyethylene glycol as a humectant, deionized water and the like, and part of couplant is matched with sterilizing disinfectant, but part of the sterilizing agent is poor in compatibility with aqueous polymer gel, so that a sterilizing product is turbid and opaque, the antibacterial effect is not ideal, and certain corrosion and stimulation effect can be generated on skin of a patient to be inspected. In recent years, in order to avoid cross infection of the ultrasonic probe in the use process, the sterilizing and disinfecting couplant gel has been developed and produced at home and abroad, so that the couplant gel has living tissue biocompatibility and biodegradability, has excellent lubricating property, and can be coated inside and outside the probe or the sheath, thereby achieving the comprehensive effects of sound transmission, lubrication, biocompatibility with living tissue and prevention of iatrogenic cross infection.
The use of an ultrasonic couplant has several purposes: firstly, the couplant eliminates air between the ultrasonic probe and the skin and eliminates the influence of the air on ultrasonic penetration; secondly, through the coupling effect of the coupling agent, the acoustic impedance difference between the ultrasonic probe and the skin is reduced, and the reflection loss of ultrasonic energy between the skin and the ultrasonic probe is reduced; thirdly, the lubrication reduces the friction between the probe surface and the skin, so that the probe can flexibly slide for probing.
The ultrasound couplant has the following requirements: (1) The sound velocity of the ultrasonic wave passing through the couplant and the sound velocity of the ultrasonic wave passing through human tissues are equal to ensure that the shape of the ultrasonic wave beam is not distorted, and if the sound velocity is not matched with the human sound velocity, artifacts or artifacts can be caused; (2) The attenuation coefficient is small, the signal to noise ratio is not reduced, and the detection of weak echo signals is facilitated; (3) Approximately equal to the acoustic characteristic impedance of human tissue to reduce reflection losses; (4) Well infiltrated with the ultrasonic probe and skin to thoroughly remove air; (5) can keep long-time wetting without drying; (6) Maintaining tackiness and adhesiveness for a longer period of time so that the probe slides smoothly along the skin; (7) Does not irritate the skin and does not cause sensitization even if contacted for a long time; (8) the appearance is attractive, water-soluble and easy to wash off; (9) The adhesion force is not reduced after the skin is smeared in clinical environment; (10) having both sound transmission and electrical insulation capabilities; (11) Has antibacterial and bacteriostatic effects on the sterilizing couplant.
The medical ultrasonic couplant conforms to the newly revised YY0299-2008 industry standard, the technical requirement standard of which is the requirement of the 5.1 th piece for biocompatibility, and the specific contents are as follows: "under contact conditions within 24 hours, the product should be non-cytotoxic" and "under contact conditions within 24 hours, the product is non-allergenic and non-irritating to the skin". In clinical practice, the couplant is typically in intimate contact with the skin. YY0299-2008 is limited from a raw material dosage form perspective, (1) excludes carboxymethyl cellulose and paraffinic oil products; (2) The alcohols are limited to nontoxic compounds such as propylene glycol, propylene glycol and polypropylene glycol, so as to eliminate certain toxicity to human bodies; (3) The requirements related to the cosmetic hygiene standard must be met to ensure the safety and non-toxicity of the formulation in terms of ingredients. There is a major requirement for toxicity to prevent skin contact poisoning. The ultrasonic couplant not only needs to meet the characteristics of chemical water-soluble gel and antibacterial and bacteriostatic properties in the field of disinfection, but also meets the characteristics of sound velocity, sound attenuation and sound impedance of the couplant in the field of ultrasonic medicine. Therefore, the couplant is required to be biocompatible with human tissue, stable and safe under ultrasonic irradiation, accords with the principles of ultrasonics and medicine, and has no damage to an ultrasonic probe.
Because of various requirements of ultrasonic couplants, the existing medical ultrasonic couplants cannot meet the requirements at the same time, how to find ultrasonic couplants meeting the characteristics of chemical water-soluble gel and antiseptic antibacterial properties and meeting the characteristics of sound velocity, sound attenuation and sound impedance of ultrasonic medicine on the couplants is a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to solve the defects in the prior art, and provides a medical ultrasonic coupling agent and a preparation method thereof.
In order to achieve the above purpose, the present invention adopts the following technical scheme: a medical ultrasound couplant comprising a couplant matrix, characterized in that: the microcapsule also comprises a microcapsule with a capsule core material as a sterilizing disinfectant, wherein the wall material of the microcapsule is a polymer formed by crosslinking citric acid/genipin and gelatin/chitosan, and the chemical structural formula of the polymer is shown as the formula (I):
in the formula (I), R1 to R9 are selected from eighteen different amino acids of glycine, alanine, serine, aspartic acid, glutamic acid amino, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine.
Preferably, in the formula (I):
r5 and R6 are selected from eighteen residues of different amino acids glycine, alanine, serine, aspartic acid, glutamine amino, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine;
r3 and R7 are residues of lysine or arginine;
r2, R4 and R8 are residues of aspartic acid or glutamic acid amino;
r1 and R9 are serine, threonine or tyrosine residues.
The invention also provides a preparation method of the medical ultrasonic couplant, which specifically comprises the following steps:
(1) Preparing an ultrasonic couplant matrix;
(2) The preparation method of the microcapsule with the capsule core material as the sterilizing disinfectant comprises the following specific steps:
a. dissolving gelatin in acetic acid aqueous solution to obtain gelatin acetic acid solution;
b. adding chitosan into gelatin acetic acid solution, stirring to dissolve chitosan to obtain gelatin chitosan mixed solution, adding sterilizing disinfectant, and adjusting pH to 5.8-6.2;
c. adding soybean lecithin as a surfactant into vegetable oil, heating and uniformly stirring;
d. adding the gelatin chitosan mixed solution prepared in the step b into the vegetable oil after the step c for heating and emulsifying, closing heating after the emulsification is completed, and naturally cooling to room temperature;
e. adding genipin solution into the solution system after the step d for crosslinking reaction, and fully completing the reaction;
f. adding a citric acid aqueous solution into the reaction system after the step e, adding glacial acetic acid, regulating the pH to 2-3, and fully reacting under the protection of N2 to obtain a microcapsule with a capsule core substance being a disinfectant aqueous solution;
(3) And (3) adding microcapsules with the capsule core material serving as sterilizing disinfectant into the system in the step (1), and thickening the system by using citric acid to prepare the medical ultrasonic coupling agent.
Preferably, the step (1) specifically includes: and heating glycerol, propylene glycol, cationic guar gum, cherry essence and deionized water in a water bath, and uniformly mixing to obtain an ultrasonic couplant matrix.
Preferably, the components in the step (1) are mixed with 5-20 parts by weight of glycerol, 5-20 parts by weight of propylene glycol, 1-2 parts by weight of cationic guar gum, 0.2-0.5 part by weight of cherry essence and the balance of deionized water.
Further preferably, the components in the step (1) are 15 parts by weight of glycerol, 15 parts by weight of propylene glycol, 1.5 parts by weight of cationic guar gum, 0.3 part by weight of cherry essence and 68.2 parts by weight of deionized water.
Preferably, the sterilizing disinfectant is polyhexamethylene guanidine hydrochloride aqueous solution or polyhexamethylene guanidine phosphate aqueous solution.
Preferably, the step f further includes: g. and d, standing the reaction system after the step f, removing the upper oil phase, centrifuging, and separating the oil phase to obtain the microcapsule with the capsule core material being the disinfectant water solution.
Preferably, in said step b, the pH is preferably adjusted to 6; in the step c, the vegetable oil is one or more of corn oil, olive oil, soybean oil and peanut oil.
Preferably, the specific steps of the step e are as follows: adding genipin water solution with the volume ratio of 0.5% into the solution system after the step d, reacting for 3 hours at room temperature, heating to 35 ℃ and reacting for 15 hours again, and fully reacting; the specific steps of the step f are as follows: adding aqueous solution of citric acid into the reaction system of the step e, adding glacial acetic acid, regulating pH to 2-3, and adding N 2 And (3) under protection, the reaction temperature is increased to 40 ℃, after the reaction is carried out for 8 hours, the reaction is cooled to room temperature, and the microcapsule with the capsule core material serving as the sterilizing disinfectant is obtained.
Preferably, the mixture ratio of the components in the step (2) is as follows: 45-55 parts of gelatin, 3-7 parts of chitosan, 250-350 parts of 1.0% acetic acid solution, 40-60 parts of soybean phospholipid, 30-40 parts of 0.5% genipin aqueous solution, 5-15 parts of 1.0% citric acid aqueous solution and 2500-3000 parts of vegetable oil. Further preferably, the composition comprises, by weight, 50 parts of gelatin, 5 parts of chitosan, 300 parts of 1.0% acetic acid solution, 50 parts of soybean phosphate, 35 parts of 0.5% genipin, 10 parts of 1.0% citric acid and 2700 parts of vegetable oil.
Preferably, the core material is 8.5-12.5 parts of disinfectant and 350-400 parts of water, and more preferably, the core material is 10 parts of disinfectant and 380 parts of water.
Preferably, the mass ratio of gelatin to chitosan is 8:1 to 12:1, the volume ratio of the water phase to the oil phase is 1:3 to 1:5, a step of; it is further preferable that the mass ratio of gelatin to chitosan is selected to be 10:1, and the volume ratio of water phase to oil phase is selected to be 1:4.
Preferably, the mass ratio of the added microcapsules to (1) is 1:1.
Compared with the prior art, the medical ultrasonic couplant has the beneficial effects that the capsule wall structure of the microcapsule has the characteristic of chemical water-soluble gel, and can meet the requirements of ultrasonic medicine on sound velocity, sound attenuation and sound impedance of the couplant, on the other hand, the capsule wall structure with a sterilizing function is only damaged when an ultrasonic head contacts and rubs, the sterilizing disinfectant is released to sterilize and disinfect contacted skin parts, and the sterilizing disinfectant which is wrapped in the capsule wall structure at skin parts without the contact and friction of the ultrasonic head is not released, so that the effective sterilizing and disinfecting effects are ensured, and the excessive stimulation effect on skin is reduced.
Drawings
FIG. 1 is an isoelectric point plot of gelatin, chitosan, and chitosan/gelatin of example 1 at different mass ratios;
FIG. 2 is a thermogravimetric plot of gelatin, chitosan, gelatin/chitosan complex, genipin cross-linked gelatin chitosan and citric acid secondary cross-linked gelatin/chitosan.
Fig. 3 shows the morphology of genipin as cross-linking agent, gelatin and chitosan as the wall of the microcapsule preparation process under microscope in example 4.
FIG. 4 is a comparison of the microscope images before and after shearing in example 4.
Fig. 5 is a graph showing the bactericidal effect of the bactericidal disinfectant prepared in example 2 on staphylococcus aureus.
FIG. 6 is a graph showing the sterilizing effect of the sterilizing disinfectant prepared in example 2 on Escherichia coli.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention.
EXAMPLE 1 isoelectric point measurement of gelatin, chitosan, gelatin-chitosan composite
1.1 isoelectric point of gelatin
0.5g of gelatin is weighed, 100ml of deionized water is added, and the mixture is stirred at a water bath temperature of 50 ℃ until the gelatin is completely dissolved, thus obtaining a gelatin solution with the concentration of 0.5%. The pH was adjusted using 0.001mol/L HCl solution and 0.001mol/L NaOH solution, and the conductivity of the gelatin solution at different pH values was recorded using a pH meter and conductivity meter.
1.2 isoelectric point of chitosan
0.5g of chitosan is weighed and added into 100ml of 0.01mol/L HCl solution, and the mixture is stirred at room temperature until the chitosan is completely dissolved, thus obtaining 0.5 percent chitosan solution. The pH of the solution was adjusted using a 0.001mol/L NaOH solution and the conductivity of the gelatin solution at different pH values was recorded using a pH meter and conductivity meter.
1.3 isoelectric point of Chitosan/gelatin composite
100mL of a 1.0% gelatin solution was placed in a beaker and magnetically stirred at a water bath temperature of 50 ℃. Adding a certain volume of 1.0% chitosan solution into the gelatin solution at the temperature of the gelatin solution, and stirring for 1h to obtain a gelatin/chitosan uniform mixed solution. The volume ratio of chitosan to gelatin is respectively as follows: 4:100, 10:100, 20: 100. 50:100, 75:100, 100:100. The pH of the mixed solution was changed using a 1.0% HCl solution and a 0.1mol/L NaOH solution, and the conductivity of the gelatin/chitosan solution was measured at different pH values using a pH meter and a conductivity meter.
The isoelectric points of the gelatin and the chitosan obtained by the measurement according to the method are shown in table 1; isoelectric curves of gelatin, chitosan and chitosan/gelatin with different mass ratios are shown in fig. 1.
TABLE 1 isoelectric points of gelatin, chitosan and different mass ratios of chitosan/gelatin isoelectric points
Example 2 preparation method of medical ultrasound couplant
(1) 15g of glycerol, 15g of propylene glycol, 2g of cationic guar gum, 0.3g of cherry essence and 67.7g of deionized water are weighed, and stirred in a water bath at 60 ℃ for 20-30min;
(2) The microcapsule with the core material being polyhexamethylene guanidine phosphate aqueous solution is prepared by the following specific steps: a. 5.0g of gelatin is weighed into a beaker, and dissolved in 30mL of 1.0% acetic acid aqueous solution at 37 ℃ in a water bath; b. after gelatin is completely dissolved, adding 0.5g of chitosan into gelatin solution, stirring and dissolving to obtain uniform gelatin/chitosan mixed solution, adding 1g of polyhexamethylene guanidine phosphate aqueous solution and 38mL of water, and adopting 5.0% ammonia water solution to adjust pH to 6;
in this step, the pH was adjusted to 6 because gelatin is an amphoteric polymer having an isoelectric point of 5.0 and a pH greater than its isoelectric point, and gelatin molecules were negatively charged, i.e., -NH 3 + Has a part of and-OH - Conversion to-NH by binding 2 whereby-COO in the gelatin molecule - (negative charge) content is greater than-NH 3 + (positively charged) content, the molecule is negatively charged. When gelatin is in a medium less than the isoelectric point, the gelatin molecule becomes positively charged, i.e. -COO - With a part of-H + Binding to-COOH, whereby-NH in a gelatin molecule 3 + A (positive charge) content of greater than-COO - (negative charge) content, the molecule is positively charged. Therefore, the pH value of the system is regulated to 6, gelatin is negatively charged, chitosan is positively charged due to the protonation of free ammonia genes on the molecules of the chitosan in an acidic medium, and therefore, the gelatin with negative charge and the chitosan with positive charge have complex coacervation reaction due to electrostatic interaction; the ionization reaction of gelatin at different pH values is shown as the formula:
the protonation reaction process of chitosan in an acidic medium is shown as a formula III:
the complex coacervation reaction of gelatin and chitosan is shown in formula IV:
c. taking 272mL of corn oil in a three-neck flask, adding 5.0g of soybean lecithin, heating to 36 ℃, and uniformly stirring, wherein the soybean lecithin is an ampholytic surfactant which can be extracted from soybeans and is natural and nontoxic;
d. adding gelatin/chitosan mixed solution into corn oil for emulsification at 600rpm and 37 ℃ for 60min;
e. closing heating, and naturally cooling to room temperature; gelatin can undergo sol-gel transition, swelling dissolution of gelatin occurs at temperatures above 35 ℃, sol-gel occurs, and gelation occurs at temperatures below 35 ℃. The temperature is reduced to the room temperature, so that the particles can form a relatively fixed shell film due to gelatin gel, the stability of the particles is improved, and the next cross-linking reaction is facilitated;
f. and d, adding 3mL of 0.5% genipin solution into the reaction system cooled in the step e, reacting for 3 hours at room temperature, and then heating to 35 ℃ to react for 15 hours.
In the step, genipin can be subjected to a crosslinking reaction with a polymer containing free amino, free amino groups on chitosan and gelatin are subjected to a hydrophilic attack on an ethylenic carbon atom at the C-3 position of genipin under an acidic condition, and a dihydropyran ring is opened to form heterocyclic amine; in addition, the ester group on genipin can be substituted with amino group to generate SN 2 Nucleophilic substitution reaction to form amide and release methanol, so as to form a three-dimensional network structure polymer taking short-chain genipin as a cross-linking bridge; the cross-linking reaction process of genipin and chitosan is shown as a formula V:
g. adding 1mL of 1% aqueous solution of citric acid into the reaction system after the step f, adding glacial acetic acid, adjusting the pH to 2-3, and adding N 2 Under the protection, the reaction temperature is raised to 40 ℃, the reaction is carried out for 8 hours, and the microcapsule with the core material of polyhexamethylene guanidine phosphate aqueous solution is obtained after cooling to room temperature;
in the step, genipin reacts with free amino groups on gelatin and chitosan to generate crosslinking, free hydroxyl groups are also present on chitosan and gelatin molecules, citric acid is added into a reaction system, under certain conditions, carboxyl groups on the citric acid and free hydroxyl groups on macromolecules generate esterification reaction, and the microcapsule taking gelatin and chitosan as capsule walls is subjected to secondary crosslinking, wherein the structural formula is shown in formula I:
h. standing the microcapsule obtained by the reaction for 2 hours, depositing gelatin/chitosan microcapsule on the lower layer, pouring corn oil on the upper layer, pouring out the upper oil phase, taking the lower layer microcapsule out, centrifuging, and separating the oil phase to obtain the microcapsule with the core material being polyhexamethylene guanidine phosphate aqueous solution. And finally transferring the microcapsule into a wide-mouth bottle, and sealing and preserving.
(3) Weighing microcapsule with core material of polyhexamethylene guanidine phosphate water solution, adding into the system of step (1), and stirring for 20-30min;
(4) Stopping heating, and cooling to room temperature under continuous stirring;
(5) And (3) dropwise adding 2% aqueous solution of citric acid into the system in the step (4), rapidly thickening the system, and continuously stirring for 30-60min to obtain the medical ultrasonic coupling agent.
Example 3 thermogravimetric analysis (TG)
3.1 analytical method
2-6mg of sample is weighed, and is tested by adopting a TG/DSC synchronous thermal analyzer, the temperature is raised from room temperature to 600 ℃ at the speed of 10 ℃/min, and the gas atmosphere is nitrogen.
3.2 analysis results
The thermal decomposition temperatures of the different samples are shown in table 2,
TABLE 2 thermal decomposition temperatures of different samples
Fig. 2 is a thermal weight graph of gelatin, chitosan, gelatin/chitosan complex, genipin cross-linked gelatin/chitosan and citric acid secondary cross-linked microcapsule, and as can be seen from table 2 and fig. 2, the thermal decomposition temperature of the microcapsule obtained by citric acid secondary cross-linking is maximum, reaching 294 ℃, and the thermal stability is higher than that of genipin primary cross-linked gelatin/chitosan. Therefore, the microcapsule wall after citric acid secondary crosslinking has higher strength and better thermal stability.
The reason for the above results is that: the citric acid secondary crosslinking microcapsule is a double crosslinking agent, genipin is adopted in the first crosslinking, and is a product of hydrolysis of geniposide by beta-glucosidase, so that the citric acid secondary crosslinking microcapsule is an excellent natural biological crosslinking agent. The second cross-linking adopts citric acid which naturally exists in fruits such as lemon and orange, one citric acid molecule contains three carboxyl groups and one hydroxyl group, and under certain reaction conditions, the citric acid can perform esterification reaction with the hydroxyl groups on gelatin and chitosan, and the gelatin/chitosan on the microcapsule wall can be further cross-linked and solidified, so that the strength of the microcapsule wall is improved, and the thermal stability of the microcapsule is improved.
Example 4 optical microscope characterization
A proper amount of the medical ultrasonic couplant prepared in example 2 was sucked up by a pipette onto a glass slide, and was observed under a model WV-CP240/G optical microscope, and photographed for recording.
Fig. 3 shows the surface morphology under a microscope in the process of preparing the microcapsule by taking genipin as a cross-linking agent and taking gelatin and chitosan as capsule walls, and as can be seen from fig. 3, in the emulsification stage, the particle size of the particles gradually becomes smaller and the particle size distribution becomes narrower with the increase of the emulsification time, and when the emulsification time reaches 60min, the particle size is smaller and the stability is better. Therefore, the time for emulsification is preferably 60 minutes. After emulsification is completed, a cross-linking agent is added for full reaction to obtain the stable gelatin/chitosan microcapsule.
A small amount of microcapsules are taken on a glass slide, the glass slide is sheared by another glass slide, a contrast image of a microscope before and after shearing is shown in fig. 4, a left image is a picture observed by the microscope before shearing, a right image is a picture observed by the microscope after shearing, and as can be seen from the picture, after shearing, a capsule wall structure is broken and a capsule core flows out. Thus, it was demonstrated that shear forces generated when the ultrasound probe was slid over the skin surface could disrupt the capsule wall structure and the polyhexamethylene guanidine phosphate was shed, completing site-directed disinfection.
Example 5 bacterial experiment
The experimental method comprises the following steps:
1. main reagent
Tryptone; yeast leaching powder; agar powder; sodium chloride; coli; staphylococcus aureus;
2. main instrument
A vertical pressure steam sterilizer; an oven; an ultra clean bench; a turbidimetry tube; a pipette gun; a culture dish; an alcohol lamp; a conical flask; a centrifuge; centrifuge tubes and the like
3. The main steps are as follows
(1) LB medium:
liquid medium:
10g of tryptone, 5g of yeast extract powder, 10g of sodium chloride and 1000mL of water are weighed into a conical flask, a glass rod is stirred for full dissolution, a conical flask mouth is sealed by a sealing film after dissolution, and the mixture is placed into a vertical pressure steam sterilizer for sterilization at 115 ℃ for 25-30min.
Solid medium:
weighing 10g of tryptone, 5g of yeast extract powder, 20g of agar powder, 10g of sodium chloride and 1000mL of water, adding into a conical flask, stirring with a glass rod under heating condition to dissolve thoroughly, sealing the conical flask mouth with a sealing film after dissolving, placing into a vertical pressure steam sterilizer, and sterilizing at 115 ℃ for 25-30min
(2) Inoculating bacteria:
firing an inoculating loop, slightly touching an original seed by the inoculating loop, inoculating the original seed into a culture medium, culturing for 18h at the constant temperature of 37 ℃, and marking.
(3) 10mL of uncooled solid culture medium is taken by a pipette, placed in a culture dish, uniformly spread and naturally cooled to form the solid culture medium.
(4) Subpackaging bacteria, centrifuging, and spreading bacteria
Centrifuge tubes were placed, each tube added 1mL of the bacteria and media mixture (liquid from the previous step), and the number was centrifuged. Centrifuging, removing supernatant, adding 1mL of physiological saline, comparing with a turbidimetric tube, and diluting with physiological saline by corresponding times to obtain bacteria with required concentration.
(5) 200 mu L of bacterial liquid is taken, beaten into one corner of a solid culture medium, then bacteria are spread by a bacteria spreader, the surface is upwards, the bottom is marked, and the solid culture medium is placed into a baking oven at 37 ℃ for culturing for 18 hours.
(6) After 18h, observing whether a bacteriostasis area exists on the solid culture medium and photographing.
Experimental results:
the sterilizing effect of the sterilizing disinfectant in the medical ultrasonic couplant prepared in example 2 on staphylococcus aureus is shown in fig. 5, and the sterilizing effect of the sterilizing disinfectant in the medical ultrasonic couplant prepared in example 2 on escherichia coli is shown in fig. 6. In fig. 5, the uppermost is a zone of inhibition generated by non-microencapsulated sterilizing agent, the middle is a zone of inhibition generated by microencapsulated and ground sterilizing agent, and the lowermost is a zone of inhibition generated by microencapsulated and non-ground sterilizing agent. As can be seen from fig. 5, the sterilizing disinfectant without microencapsulation produces the most excellent sterilizing performance, and the sterilizing disinfectant with microencapsulation and grinding treatment produces little sterilizing performance due to the coating of the wall material because grinding does not ensure the breakage of the whole microcapsules. FIG. 6 shows the sterilizing effect on E.coli, wherein the uppermost part is a zone of inhibition generated by the sterilizing disinfectant which is microencapsulated but not ground, the middle part is a zone of inhibition generated by the sterilizing disinfectant which is not microencapsulated, and the lowermost part is a zone of inhibition generated by the sterilizing disinfectant which is microencapsulated and ground. As can be seen from FIG. 6, the same effect was exhibited on Escherichia coli as compared with the bactericidal activity against Staphylococcus aureus.
This experiment demonstrates that: (1) The sterilizing disinfectant in the coupling agent has good sterilizing effect on staphylococcus aureus and escherichia coli; (2) The sterilization disinfectant can be successfully coated by microencapsulation; (3) The microcapsule breaks after being stressed, and the capsule core material has sterilizing effect after flowing out.
Example 5 solids content determination
The measuring method comprises the following steps:
about 1.000g of the couplant sample is weighed in a sample bottle, placed in a 50 ℃ oven for 3 hours, the residual mass is weighed, the solid content of the sample at 50 ℃ is calculated through a formula (1), and three groups of parallel experiments are performed to avoid the accident of the experiment. A series of experiments were also performed on the solids content of the samples at 105 ℃.
Wherein: m' is the mass of the sample and sample bottle remaining after the reaction is completed, in g; m is the mass of the sample bottle in g; m is m 0 Is the mass of the initial sample in g.
Solid content measurement results:
the sample solid content of the conventional medical ultrasonic couplant measured by the above measurement method is shown in table 3, and the measured sample solid content of the medical ultrasonic couplant prepared in example 2 is shown in table 4.
Table 3 solid content of conventional medical ultrasonic couplant sample
Table 4 solid content of medical ultrasonic couplant sample prepared in example 2
Example 6 Acoustic Properties
The couplant prepared in example 2 was a light-colored transparent gel having an acoustic velocity of 1562m/s (standard 1520-1620 m/s), an acoustic impedance of 1.61X 106 Pa.s/m (standard 1.5X106-1.7X106 Pa.s/m), and an acoustic attenuation of 0.026 Db/(cm. MHz) (standard 0.05 Db/(cm. MHz) or less).
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by equally replacing or changing the technical scheme and the inventive concept thereof.

Claims (10)

1. The preparation method of the medical ultrasonic coupling agent is characterized by comprising the following steps of:
(1) Preparing an ultrasonic couplant matrix;
(2) The preparation method of the microcapsule with the capsule core material as the sterilizing disinfectant comprises the following specific steps:
a. dissolving gelatin in acetic acid aqueous solution to obtain gelatin acetic acid solution;
b. adding chitosan into gelatin acetic acid solution, stirring to dissolve chitosan to obtain gelatin chitosan mixed solution, adding sterilizing disinfectant, and adjusting pH to 5.8-6.2;
c. adding soybean lecithin as a surfactant into vegetable oil, heating and uniformly stirring;
d. adding the gelatin chitosan mixed solution prepared in the step b into the vegetable oil after the step c for heating and emulsifying, closing heating after the emulsification is completed, and naturally cooling to room temperature;
e. adding genipin solution into the solution system after the step d for crosslinking reaction, and fully completing the reaction;
f. adding aqueous solution of citric acid and glacial acetic acid into the reaction system after the step e, and regulatingpH is 2-3, in N 2 Fully reacting under protection to obtain microcapsules with capsule core materials as sterilizing disinfectant aqueous solution;
(3) And (3) adding microcapsules with the capsule core material serving as sterilizing disinfectant into the system in the step (1), and thickening the system by using citric acid to prepare the medical ultrasonic coupling agent.
2. The method for preparing a medical ultrasound couplant according to claim 1, wherein the step (1) specifically comprises: and heating glycerol, propylene glycol, cationic guar gum, cherry essence and deionized water in a water bath, and uniformly mixing to obtain an ultrasonic couplant matrix.
3. The method for preparing the medical ultrasonic coupling agent according to claim 1, wherein the components in the step (1) are mixed according to parts by weight: 5-20 parts of glycerol, 5-20 parts of propylene glycol, 1-2 parts of cationic guar gum, 0.2-0.5 part of cherry essence and the balance of deionized water.
4. The method for preparing a medical ultrasonic couplant according to claim 1, wherein the sterilizing disinfectant is polyhexamethylene guanidine hydrochloride aqueous solution or polyhexamethylene guanidine phosphate aqueous solution.
5. The method for preparing a medical ultrasound couplant according to claim 1, wherein after step f, further comprises: g. and d, standing the reaction system after the step f, pouring out the upper oil phase, centrifuging, and separating out the oil phase to obtain the microcapsule with the capsule core material being the disinfectant water solution.
6. The method for preparing a medical ultrasound couplant according to claim 1, wherein in step b, pH is adjusted to 6; in the step c, the vegetable oil is one or more of corn oil, olive oil, soybean oil and peanut oil.
7. The method for preparing a medical ultrasonic couplant according to claim 1, which comprisesIs characterized in that the specific steps of the step e are as follows: adding genipin water solution with the volume ratio of 0.5% into the solution system after the step d, reacting for 3 hours at room temperature, heating to 35 ℃ and reacting for 15 hours again, and fully reacting; the specific steps of the step f are as follows: adding aqueous solution of citric acid into the reaction system of the step e, adding glacial acetic acid, regulating pH to 2-3, and adding N 2 And (3) under protection, the reaction temperature is increased to 40 ℃, after the reaction is carried out for 8 hours, the reaction is cooled to room temperature, and the microcapsule with the capsule core material serving as the sterilizing disinfectant is obtained.
8. The method for preparing the medical ultrasonic coupling agent according to claim 1, wherein the proportion of each component in the step (2) is as follows: 45-55 parts of gelatin, 3-7 parts of chitosan, 250-350 parts of 1.0% acetic acid solution, 40-60 parts of soybean phospholipid, 30-40 parts of 0.5% genipin aqueous solution, 5-15 parts of 1.0% citric acid aqueous solution and 2500-3000 parts of vegetable oil.
9. The medical ultrasonic couplant prepared by the method for preparing the medical ultrasonic couplant according to any one of claims 1-8, comprising a couplant matrix, characterized in that: the microcapsule also comprises a microcapsule with a capsule core material as a sterilizing disinfectant, wherein the wall material of the microcapsule is a polymer formed by crosslinking citric acid/genipin and gelatin/chitosan, and the chemical structural formula of the polymer is shown as the formula (I):
in the formula (I), R is 1 To R 9 One of the residues selected from eighteen different amino acids glycine, alanine, serine, aspartic acid, glutamic acid amino, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine.
10. The medical ultrasound couplant of claim 9, wherein in the formula (I):
R 5 、R 6 residues selected from eighteen different amino acids glycine, alanine, serine, aspartic acid, glutamic acid amino group, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine;
R 3 、R 7 residues that are lysine or arginine;
R 2 、R 4 、R 8 residues that are aspartic acid or glutamic acid amino groups;
R 1 、R 9 residues that are serine, threonine or tyrosine.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009064A1 (en) * 2007-07-09 2009-01-15 Orison Corporation Ultrasound coupling material
WO2020209909A1 (en) * 2019-04-12 2020-10-15 International Flavors & Fragrances Inc. Sustainable core-shell microcapsules prepared with combinations of cross-linkers
CN112275228A (en) * 2020-10-15 2021-01-29 中国科学院重庆绿色智能技术研究院 Method for preparing multi-layer capsule wall microcapsule based on complex coacervation method and product

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009009064A1 (en) * 2007-07-09 2009-01-15 Orison Corporation Ultrasound coupling material
WO2020209909A1 (en) * 2019-04-12 2020-10-15 International Flavors & Fragrances Inc. Sustainable core-shell microcapsules prepared with combinations of cross-linkers
CN112275228A (en) * 2020-10-15 2021-01-29 中国科学院重庆绿色智能技术研究院 Method for preparing multi-layer capsule wall microcapsule based on complex coacervation method and product

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Double crosslinked chitosan and gelatin submicronic capsules entrapping aminoacid derivatives with potential antitumoral activity;Mihaela Moise等;《J Mater Sci.》;第47卷;8223-8233 *

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