CN115040666A - Medical ultrasonic coupling agent and preparation method thereof - Google Patents
Medical ultrasonic coupling agent and preparation method thereof Download PDFInfo
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- CN115040666A CN115040666A CN202111190846.2A CN202111190846A CN115040666A CN 115040666 A CN115040666 A CN 115040666A CN 202111190846 A CN202111190846 A CN 202111190846A CN 115040666 A CN115040666 A CN 115040666A
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The invention provides a medical ultrasonic couplant and a preparation method thereof, the medical ultrasonic couplant contains microcapsules with capsule core substances as sterilizing disinfectants, the capsule wall structure of the microcapsules has chemical water-soluble gel characteristics and can meet the requirements of sound velocity, sound attenuation and sound impedance characteristics of ultrasonic medicine on the couplant, on the other hand, the sterilizing disinfectants with sterilizing effect are wrapped in the capsule wall structure with certain mechanical properties, the capsule wall structure is damaged when an ultrasonic probe is in contact friction, the sterilizing disinfectants are released to sterilize and disinfect contacted skin parts, and the sterilizing disinfectants wrapped in the capsule wall structure on the skin parts without the contact friction of the ultrasonic probe are not released, so that the effective sterilizing and disinfecting effect is ensured, and the excessive stimulation effect on the skin is reduced.
Description
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, the antagonism difference between the ultrasonic probe and the skin is large due to the existence of air, and the ultrasonic wave emitted by the ultrasonic probe cannot pass through the skin and enter a human body, so that the medical ultrasonic coupling agent is produced by transportation and is smeared between the ultrasonic probe and the surface of the skin, and 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 the skin of a human body and establishes a coupling effect between the probe and the skin of the human body so that ultrasonic waves can be smoothly transmitted into the human body to obtain reliable detection and diagnosis images or achieve the purpose of effective treatment, and is a medium required to be used in the ultrasonic diagnosis and treatment process. The ultrasonic couplant plays an important role in the ultrasonic diagnosis and treatment process, plays a role of a lubricant besides the role of a medium, does not only pay attention to the acoustic characteristics in clinical application, and also has effectiveness and safety. Wherein, the effectiveness mainly refers to the sound transmission effect, and the safety mainly refers to the influence on human tissues and the prevention of cross infection.
The traditional ultrasonic coupling agent has no disinfection and bacteriostasis functions, so that a pathogenic bacteria propagation channel is formed between an ultrasonic probe and the skin of a human body, and the problem of multiple bacterial infection in the ultrasonic diagnosis and treatment process is caused. Therefore, the preparation of the disinfection type medical ultrasonic couplant instead of the traditional medical ultrasonic couplant is an intervention measure which is widely popularized at present. The 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 moisturizing agent, deionized water and the like, wherein part of couplant is prepared from a sterilizing disinfectant, but part of the sterilizing agent and water-based polymer gel have poor phase solubility, so that the sterilizing product is turbid and opaque, the antibacterial effect is not ideal, and certain corrosion and stimulation effects can be generated on the skin of a patient to be examined. In recent years, in order to avoid cross infection of the ultrasonic probe in the use process, a disinfection and sterilization type coupling agent gel has been developed and produced at home and abroad, so that the coupling agent gel has biological compatibility and biodegradability of living tissues, has excellent lubrication property, and can be coated on the inside and outside of the probe or sheath, thereby achieving the comprehensive effects of sound transmission, lubrication, biological compatibility with the living tissues and prevention of iatrogenic cross infection.
The use of an ultrasonic coupling agent has several purposes: firstly, the couplant removes air between the ultrasonic probe and the skin, and eliminates the influence of the air on ultrasonic penetration; secondly, the acoustic impedance difference between the ultrasonic probe and the skin is reduced through the coupling effect of the coupling agent, and the reflection loss of the ultrasonic energy between the skin and the ultrasonic probe is reduced; thirdly, the friction between the probe surface and the skin is reduced by the lubrication effect, so that the probe can flexibly slide for probing.
The ultrasonic coupling agent has the following requirements: (1) the sound velocity of the ultrasonic waves passing through the couplant and the sound velocity of the ultrasonic waves passing through human tissue should be equal to ensure that the shape of the ultrasonic beam is not distorted, and artifacts or artifacts can be caused if the sound velocity is not matched with the sound velocity of the human body; (2) the attenuation coefficient is small, the signal-to-noise ratio is not reduced, and the weak echo signal can be detected; (3) the impedance is approximately equal to the acoustic characteristic impedance of human tissue so as to reduce reflection loss; (4) well infiltrate with the ultrasonic probe and the skin to completely remove air; (5) can keep wet for a long time without drying; (6) the viscosity and adhesiveness are kept for a long time, so that the probe can smoothly slide along the skin; (7) does not irritate the skin and does not cause sensitization reaction even if contacted for a long time; (8) the appearance is beautiful, the water-soluble paint is water-soluble and can be easily washed off; (9) the adhesion force is not reduced after the skin-care cream is smeared on the skin in a clinical environment; (10) the acoustic transmission and electric insulation capabilities are achieved; (11) it has antibacterial and bacteriostatic effects on the disinfectant couplant.
The medical ultrasonic couplant follows a newly revised YY0299-2008 industry standard, and the 5.1 th technical requirement standard thereof is the requirement of biocompatibility, and the specific contents are as follows: under the condition of contacting within 24h, the product has no cytotoxicity, and under the condition of contacting within 24h, the product has no sensitization and stimulation to skin. In clinical practice, the coupling agent generally needs to be in intimate contact with the skin. YY0299-2008 imposes limitations from a raw material dosage form perspective, (1) excludes carboxymethylcellulose and paraffin oil products; (2) the contained alcohols are limited to propylene glycol, polypropylene glycol and other nontoxic compounds so as to eliminate certain toxicity to human bodies; (3) must meet the relevant requirements in the cosmetic hygiene standards and ensure the safety and non-toxicity of the preparation from the aspect of ingredients. Certain requirements are made mainly on toxicity, and skin contact poisoning is prevented. The ultrasonic couplant not only needs to meet the characteristics of water-soluble gel in chemistry and antibacterial and bacteriostatic properties in disinfection, but also needs to meet the sound velocity, sound attenuation and sound impedance characteristics of the couplant in ultrasonic medicine. Therefore, the coupling agent is required to be biocompatible with human tissues, stable and safe under ultrasonic irradiation, conforms to the principles of ultrasonics and medicine, and has no damage to an ultrasonic probe.
Due to various requirements of ultrasonic coupling agents, the existing medical ultrasonic coupling agents cannot meet the requirements at the same time, and how to search for the ultrasonic coupling agent which meets the water-soluble gel characteristics in chemistry and the antibacterial and bacteriostatic characteristics in disinfection, and also meets the sound velocity, sound attenuation and sound impedance characteristics of the coupling agent in ultrasonic medicine becomes a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a medical ultrasonic couplant and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme: a medical ultrasonic couplant comprises a couplant matrix, and is characterized in that: the microcapsule also comprises a microcapsule with a capsule core substance 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-R9 are selected from one of the residues of eighteen different amino acids glycine, alanine, serine, aspartic acid, glutamic amino acid, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine.
Preferably, in said formula (I):
r5 and R6 are selected from one of eighteen different amino acid residues of glycine, alanine, serine, aspartic acid, glutamic amino acid, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine;
r3, R7 are residues of lysine or arginine;
r2, R4 and R8 are residues of aspartic acid or glutamic acid amino;
r1, R9 are residues of serine, threonine or tyrosine.
The invention also provides a preparation method of the medical ultrasonic coupling agent, which comprises the following steps:
(1) preparing an ultrasonic coupling agent matrix;
(2) the preparation method of the microcapsule with the core material as the bactericidal disinfectant comprises the following specific steps:
a. dissolving gelatin in acetic acid water 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 disinfectant, and adjusting pH to 5.8-6.2;
c. adding surfactant soybean phospholipid into vegetable oil, heating, and stirring;
d. c, adding the gelatin chitosan mixed solution prepared in the step b into the vegetable oil obtained in the step c, heating and emulsifying, turning off the heating after the emulsification is finished, and naturally cooling to room temperature;
e. d, adding a genipin solution into the solution system obtained in the step d to perform a crosslinking reaction, and fully reacting;
f. adding a citric acid aqueous solution into the reaction system obtained in the step e, adding glacial acetic acid, adjusting the pH to 2-3, and fully reacting under the protection of N2 to obtain microcapsules with capsule core substances of the bactericidal disinfectant aqueous solution;
(3) and (2) adding microcapsules with a capsule core substance of a bactericidal disinfectant into the system in the step (1), and thickening the system by using citric acid to prepare the medical ultrasonic couplant.
Preferably, the step (1) is specifically: heating glycerol, propylene glycol, cationic guar gum, cherry essence and deionized water in a water bath, and uniformly mixing to obtain the ultrasonic couplant matrix.
Preferably, the components in the step (1) comprise, by mass, 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.
Further preferably, the mixture ratio of each component in the step (1) is 15 parts of glycerol, 15 parts of propylene glycol, 1.5 parts of cationic guar gum, 0.3 part of cherry essence and 68.2 parts of deionized water by mass.
Preferably, the germicidal sterilant is an aqueous solution of polyhexamethylene guanidine hydrochloride or polyhexamethylene guanidine phosphate.
Preferably, step f is followed by: g. and f, 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 substance being the aqueous solution of the bactericidal disinfectant.
Preferably, in 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 step e are: d, adding 0.5% by volume of genipin aqueous solution into the solution system obtained in the step d, reacting for 3 hours at room temperature, heating to 35 ℃, reacting for 15 hours again, and reacting fully; the specific steps of the step f are as follows: adding citric acid aqueous solution into the reaction system in the step e, adding glacial acetic acid, adjusting the pH to 2-3, and adding N 2 Under protection, the reaction temperature is raised to 40 ℃, and after 8 hours of reaction, the reaction is cooled to room temperature, so that the microcapsule with the capsule core material as the sterilizing disinfectant is obtained.
Preferably, the ratio of each component in the step (2) is as follows according to parts by weight: 45-55 parts of gelatin, 3-7 parts of chitosan, 350 parts of 1.0% acetic acid solution 250-ion, 40-60 parts of soybean lecithin, 30-40 parts of 0.5% genipin aqueous solution, 5-15 parts of 1.0% citric acid aqueous solution and 3000 parts of vegetable oil 2500-ion. More preferably, the weight parts of the composition are 50 parts of gelatin, 5 parts of chitosan, 300 parts of 1.0% acetic acid solution, 50 parts of soybean phospholipid, 35 parts of 0.5% genipin, 10 parts of 1.0% citric acid and 2700 parts of vegetable oil.
Preferably, the capsule core material is 8.5-12.5 parts of germicidal sterilant and 350-400 parts of water, and further preferably, the capsule core material is 10 parts of germicidal sterilant 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; further preferably, 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 added microcapsules to (1) is 1: 1.
Compared with the prior art, the medical ultrasonic couplant has the beneficial effects that the medical ultrasonic couplant contains microcapsules of which the capsule core substances are the bactericidal disinfectant, the capsule wall structure of the microcapsules has the chemical water-soluble gel characteristic, and the requirements of ultrasonic medicine on the sound velocity, sound attenuation and sound impedance characteristics of the couplant can be met, on the other hand, the bactericidal disinfectant with the disinfection effect is wrapped in the capsule wall structure with certain mechanical performance, the capsule wall structure is damaged when an ultrasonic head is in contact friction, the bactericidal disinfectant is released to sterilize and disinfect contacted skin parts, and the bactericidal disinfectant wrapped in the capsule wall structure on the skin parts without the contact friction of the ultrasonic head is not released, so that the effective sterilization and disinfection effect is ensured, and the excessive stimulation effect on the skin is reduced.
Drawings
FIG. 1 is a graph of isoelectric point curves for 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 is a microscopic image of a process of preparing a microcapsule with genipin as a cross-linking agent, gelatin and chitosan as capsule walls in example 4.
FIG. 4 is a microscopic comparison of before and after shearing in example 4.
FIG. 5 is a graph showing the bactericidal effect of the disinfectant prepared in example 2 on Staphylococcus aureus.
FIG. 6 is a graph showing the bactericidal effect of the bactericidal 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 determination of isoelectric Point of gelatin, Chitosan, gelatin Chitosan composite
1.1 isoelectric Point of gelatin
0.5g of gelatin is weighed, added with 100ml of deionized water and stirred at the water bath temperature of 50 ℃ until the gelatin is completely dissolved, thus obtaining a 0.5% gelatin solution. 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 points of Chitosan
0.5g of chitosan was weighed, added to 100ml of 0.01mol/L HCl solution, and stirred at room temperature until chitosan was completely dissolved, to obtain a 0.5% chitosan solution. The pH of the solution was adjusted using 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 points of chitosan/gelatin composite materials
100mL of 1.0% gelatin solution was placed in a beaker and magnetically stirred at a bath temperature of 50 deg.C. Adding a certain volume of 1.0% chitosan solution into the gelatin solution, and stirring for 1h to obtain a gelatin/chitosan uniform mixed solution. The volume ratio of the chitosan to the 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 1.0% HCl solution and 0.1mol/L NaOH solution, and the conductivity of the gelatin/chitosan solution at different pH values was measured using a pH meter and a conductivity meter.
The isoelectric points of the gelatin and the chitosan obtained by the method and the isoelectric points of the chitosan/gelatin with different mass ratios are shown in table 1; the isoelectric point curves of gelatin, chitosan and chitosan/gelatin in different mass ratios are shown in figure 1.
TABLE 1 isoelectric points of gelatin, chitosan and chitosan/gelatin in different mass ratios
Example 2 preparation method of medical ultrasonic coupling agent
(1) Weighing 15g of glycerol, 15g of propylene glycol, 2g of cationic guar gum, 0.3g of cherry essence and 67.7g of deionized water, and stirring in a water bath at 60 ℃ for 20-30 min;
(2) the preparation method of the microcapsule with the core material of polyhexamethylene guanidine phosphate aqueous solution comprises the following specific steps: weighing 5.0g of gelatin in a beaker, dissolving in 30mL of 1.0% acetic acid aqueous solution at the water bath temperature of 37 ℃; b, when the gelatin is completely dissolved, adding 0.5g of chitosan into the gelatin solution, stirring and dissolving to obtain a uniform gelatin/chitosan mixed solution, adding 1g of polyhexamethylene guanidine phosphate aqueous solution and 38mL of water, and adjusting the pH to 6 by adopting 5.0% ammonia water solution;
in this step, the pH is adjusted to 6 because gelatin is an amphoteric polymer having an isoelectric point of 5.0, and gelatin molecules exhibit negative charges, i.e., -NH, at a pH above its isoelectric point 3 + Having a portion with-OH - Combined to convert into-NH 2 thus-COO in the gelatin molecule - (negative charge) content greater than-NH 3 + (positive charge) content, the molecule shows negative charge. When gelatin is in a medium less than the isoelectric point, the gelatin molecule is positively charged, i.e., -COO - Having a portion of and-H + Binding conversion to-COOH, thereby-NH in the gelatin molecule 3 + (Positive charge) content greater than-COO - (negative charge) content, the molecule is positively charged. Therefore, the pH value of the system is adjusted to 6, the gelatin is negatively charged, the chitosan is positively charged due to protonation of free ammonia genes on the molecules in an acid medium, and the negatively charged gelatin and the positively charged chitosan are subjected to complex coacervation due to electrostatic interactionCarrying out reaction; the ionization reaction of gelatin at different pH values is shown by 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 as formula IV:
c. putting 272mL corn oil into a three-neck flask, adding 5.0g soybean phospholipid, heating to 36 ℃, and uniformly stirring, wherein the soybean phospholipid is an amphoteric 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, 37 deg.C for 60 min;
e. turning off heating, and naturally cooling to room temperature; gelatin can be subjected to sol-gel transition, and when the temperature is higher than 35 ℃, the gelatin swells and dissolves, so that sol occurs, and when the temperature is lower than 35 ℃, the gelatin gels. The temperature is reduced to 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 step of crosslinking reaction is facilitated;
f. and e, adding 3mL of 0.5% genipin solution into the reaction system cooled in the step e, reacting at room temperature for 3 hours, and then heating to 35 ℃ for reaction for 15 hours.
In the step, genipin can generate cross-linking reaction with the free amino-containing polymer, and under the acidic condition,free amino groups on the chitosan and the gelatin attack alkene carbon atoms at the C-3 position of the genipin, and a dihydropyran ring is opened to form heterocyclic amine; in addition, ester group on genipin can generate SN with amino 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 formula V:
g. adding 1mL of 1% citric acid aqueous solution into the reaction system after the step f, adding glacial acetic acid, adjusting the pH to 2-3, and adding N 2 Under protection, the reaction temperature is raised to 40 ℃, the reaction is carried out for 8 hours, and the microcapsule with the core substance 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 also exist on chitosan and gelatin molecules, citric acid is added into a reaction system, under a certain condition, carboxyl groups on the citric acid and the free hydroxyl groups on macromolecules generate esterification reaction, and the microcapsules taking the gelatin and the chitosan as capsule walls are subjected to secondary crosslinking, wherein the structural formula is shown as formula I:
h. standing the microcapsule obtained by the reaction for 2h, depositing the gelatin/chitosan microcapsule on the lower layer, pouring out the oil phase on the upper layer, taking out the microcapsule on the lower layer, centrifuging, and separating out the oil phase to obtain the microcapsule with the core material of polyhexamethylene guanidine phosphate aqueous solution. And finally, transferring the microcapsules into a wide-mouth bottle, and sealing and storing.
(3) Weighing microcapsules of which the core substances are polyhexamethylene guanidine phosphate aqueous solution, adding the microcapsules into the system obtained in the step (1), and stirring for 20-30 min;
(4) stopping heating, and cooling to room temperature under continuous stirring;
(5) and (4) dropwise adding 2% citric acid aqueous solution into the system in the step (4), quickly thickening the system, and continuously stirring for 30-60min to obtain the medical ultrasonic coupling agent.
Example 3 thermogravimetric analysis (TG)
3.1 analytical methods
Weighing 2-6mg of sample, testing by adopting a TG/DSC synchronous thermal analyzer, heating from room temperature to 600 ℃ at the speed of 10 ℃/min, and taking nitrogen as gas atmosphere.
3.2 results of analysis
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 thermogravimetric graph of gelatin, chitosan, gelatin/chitosan complex, genipin cross-linked gelatin/chitosan and citric acid secondary cross-linked microcapsule, and it can be seen from table 2 and fig. 2 that the temperature of thermal decomposition of the microcapsule obtained by citric acid secondary cross-linking is the largest, reaching 294 ℃, and the thermal stability is higher than that of genipin primary cross-linked gelatin/chitosan. Therefore, the microcapsule wall subjected to citric acid secondary crosslinking has higher strength and better thermal stability.
The reason for the above results is: the microcapsule of the citric acid secondary cross-linking is a double cross-linking agent, genipin is adopted for the first cross-linking, and genipin is a product of geniposide hydrolyzed by beta-glucosidase and is an excellent natural biological cross-linking agent. The second cross-linking adopts citric acid which naturally exists in fruits such as citrus and the like, one citric acid molecule contains three carboxyl groups and one hydroxyl group, under a certain reaction condition, the citric acid can be subjected to esterification reaction with the hydroxyl groups on the gelatin and the chitosan, and the gelatin/chitosan on the capsule wall of the microcapsule can be further cross-linked and solidified, so that the strength of the capsule wall is improved, and the thermal stability of the microcapsule is increased.
Example 4 optical microscopy characterization
An appropriate amount of the medical ultrasonic couplant prepared in example 2 was pipetted onto a glass slide, observed under a WV-CP240/G optical microscope, and recorded by photographing.
Fig. 3 shows the microscopic surface morphology of the microcapsule prepared by using genipin as a cross-linking agent and 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 decreases and the particle size distribution becomes narrow 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 emulsifying time is preferably 60 min. And after emulsification is finished, adding a cross-linking agent, and fully reacting to obtain the stable gelatin/chitosan microcapsule.
A small amount of microcapsules are taken out of a glass slide, the glass slide is sheared by another glass slide, and a contrast picture of a microscope before and after shearing is shown in figure 4, the left picture is a picture observed by the microscope before shearing, the right picture 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 can rupture the capsule wall structure and polyhexamethylene guanidine phosphate flowed out to accomplish site directed disinfection.
Example 5 bacterial experiments
The experimental method comprises the following steps:
1. primary reagent
Tryptone; extracting yeast powder; agar powder; sodium chloride; e.coli; staphylococcus aureus bacteria;
2. main instrument
A vertical pressure steam sterilizer; baking oven; an ultra-clean bench; a turbidimetric tube; a liquid transferring gun; a culture dish; an alcohol lamp; a conical flask; a centrifuge; centrifuge tubes and the like
3. The main steps are
An LB culture medium:
liquid culture medium:
weighing 10g of tryptone, 5g of yeast extract powder, 10g of sodium chloride and 1000mL of water, adding the weighed materials into a conical flask, stirring by a glass rod to fully dissolve, sealing the opening of the conical flask by a sealing film after the materials are dissolved, putting the conical flask into a vertical pressure steam sterilizer, and sterilizing for 25-30min at 115 ℃.
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 by a glass rod under heating to fully dissolve, sealing the conical flask opening by a sealing film after dissolving, placing into a vertical pressure steam sterilizer, and sterilizing at 115 ℃ for 25-30min
② inoculating bacteria:
firing the inoculating loop, lightly touching the original seed with the inoculating loop, inoculating into a culture medium, culturing at a constant temperature of 37 ℃ for 18h, and marking.
And thirdly, taking 10mL of uncooled solid culture medium by using a pipette, putting the uncooled solid culture medium into a culture dish, uniformly spreading the uncooled solid culture medium, and naturally cooling the uncooled solid culture medium to form the solid culture medium.
Fourthly, subpackaging the bacteria, centrifuging and spreading the bacteria
Place the tubes and add 1mL of the bacteria and media mixture (liquid from previous step) to each tube, and number centrifuge. And centrifuging, removing supernatant, adding 1mL of normal saline, comparing with a turbidimetric tube, and diluting by corresponding times with the normal saline to obtain the bacteria with the required concentration.
Fifthly, taking 200 mu L of the bacterial liquid, beating the bacterial liquid to one corner of a solid culture medium, then spreading bacteria by a bacteria spreader, enabling the surface to be upward and the bottom to be marked, and putting the bacteria into an oven at 37 ℃ for culturing for 18 hours.
And sixthly, observing whether a bacteriostatic circle exists on the solid culture medium after 18 hours and taking a picture.
The experimental results are as follows:
the sterilization effect of the disinfectant in the medical ultrasonic couplant prepared in example 2 on staphylococcus aureus is shown in fig. 5, and the sterilization effect of the disinfectant in the medical ultrasonic couplant prepared in example 2 on escherichia coli is shown in fig. 6. In fig. 5, the uppermost zone is the zone of inhibition by the non-microencapsulated bactericide, the middle zone is the zone of inhibition by the microencapsulated and ground bactericidal disinfectant, and the lowermost zone is the zone of inhibition by the microencapsulated but non-ground bactericidal disinfectant. As can be seen from fig. 5, the maximal bactericidal performance of the zone of inhibition generated by the non-microencapsulated bactericidal disinfectant is the best, the zone of inhibition generated by the microencapsulated and ground bactericidal disinfectant is smaller than that of the non-microencapsulated disinfectant, and the grinding can not guarantee the microcapsules to be completely broken, so the bactericidal performance is reduced, and the microencapsulated and non-ground bactericidal disinfectant hardly generates the zone of inhibition due to the coating of the wall material. FIG. 6 shows the bactericidal effect on Escherichia coli, the uppermost zone being the zone of inhibition by the microencapsulated but unground bactericidal disinfectant, the middle zone being the zone of inhibition by the ungelled bactericidal disinfectant, and the lowermost zone being the zone of inhibition by the microencapsulated and ground bactericidal disinfectant. As can be seen from FIG. 6, the bactericidal activity against Escherichia coli was also similar to that against Staphylococcus aureus.
The experiment can prove that: (1) the bactericidal disinfectant in the coupling agent has good bactericidal effect on staphylococcus aureus and enterobacter coli; (2) the sterilization disinfectant can be successfully coated by microencapsulation; (3) the microcapsule is broken after being stressed, and the capsule core substance has bactericidal effect after flowing out.
Example 5 determination of solid content
The determination method comprises the following steps:
weighing about 1.000g of couplant sample in a sample bottle, placing the sample in a 50 ℃ oven for 3h, weighing the residual mass, calculating the solid content of the sample at 50 ℃ according to the formula (1), and performing three groups of parallel experiments to avoid the accidental experiments. A further set of experiments was performed on the solids content of the samples at 105 ℃.
In the formula: m' is the mass of the residual sample and sample bottle after the reaction is finished, and the unit is g; m is the sample vial mass in g; m is a unit of 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 measuring method is shown in table 3, and the sample solid content of the medical ultrasonic couplant prepared in example 2 is shown in table 4.
TABLE 3 solid content of conventional medical ultrasound coupling agent sample
Table 4 solid content of sample of ultrasound coupling agent for medical use prepared in example 2
Example 6 Acoustic Properties
The couplant prepared in example 2 is light-colored transparent gel, sound velocity is 1562m/s (1520-1620 m/s), acoustic impedance is 1.61X 106 Pa.s/m (1.5X 106-1.7X 106 Pa.s/m), and acoustic attenuation is 0.026 Db/(cm.MHz) (0.05 Db/(cm.MHz) or less).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention, the technical solutions and the inventive concepts of the present invention with equivalent or modified alternatives and modifications within the technical scope of the present invention.
Claims (10)
1. A medical ultrasonic couplant comprises a couplant matrix and is characterized in that: the microcapsule also comprises a microcapsule with a core substance as a sterilizing disinfectant, 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-R9 are selected from one of residues of 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.
2. The medical ultrasound couplant of claim 1, wherein: in the formula (I):
r5 and R6 are selected from one of residues of eighteen different amino acids of glycine, alanine, serine, aspartic acid, glutamic amino acid, proline, arginine, histidine, tyrosine, cystine, leucine, threonine, methionine, valine, phenylalanine, tryptophan, glutamic acid and lysine;
r3, R7 are residues of lysine or arginine;
r2, R4 and R8 are residues of aspartic acid or glutamic acid amino groups;
r1, R9 are residues of serine, threonine or tyrosine.
3. A preparation method of a medical ultrasonic coupling agent specifically comprises the following steps:
(1) preparing an ultrasonic coupling agent matrix;
(2) the preparation method of the microcapsule with the core material as the bactericidal disinfectant comprises the following specific steps:
a. dissolving gelatin in acetic acid water 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 disinfectant, and adjusting pH to 5.8-6.2;
c. adding soybean phospholipid as surfactant into vegetable oil, heating, and stirring;
d. c, adding the gelatin chitosan mixed solution prepared in the step b into the vegetable oil obtained in the step c, heating and emulsifying, turning off the heating after the emulsification is finished, and naturally cooling to room temperature;
e. d, adding a genipin solution into the solution system obtained in the step d to perform a crosslinking reaction, and fully reacting;
f. adding a citric acid aqueous solution into the reaction system obtained in the step e, adding glacial acetic acid, adjusting the pH to 2-3, and fully reacting under the protection of N2 to obtain microcapsules with capsule core substances of the bactericidal disinfectant aqueous solution;
(3) and (2) adding microcapsules taking capsule core substances as the bactericidal disinfectant into the system in the step (1), and thickening the system by using citric acid to prepare the medical ultrasonic coupling agent.
4. The preparation method of the medical ultrasonic couplant according to claim 3, wherein the step (1) is specifically as follows: heating glycerol, propylene glycol, cationic guar gum, cherry essence and deionized water in a water bath, and uniformly mixing to obtain the ultrasonic couplant matrix.
5. The preparation method of the medical ultrasonic couplant according to claim 4, wherein the components in the step (1) are, by mass, 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.
6. The method for preparing a medical ultrasound couplant according to claim 3, wherein the germicidal sterilant is an aqueous solution of polyhexamethylene guanidine hydrochloride or an aqueous solution of polyhexamethylene guanidine phosphate.
7. The method for preparing a medical ultrasound couplant according to claim 3, further comprising, after step f: g. and f, 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 substance being the aqueous solution of the bactericidal disinfectant.
8. The method for preparing the medical ultrasound couplant according to claim 3, wherein in the 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.
9. The preparation method of the medical ultrasonic couplant according to claim 3, wherein the specific steps of the step e are as follows: d, adding 0.5% by volume of genipin aqueous solution into the solution system obtained in the step d, reacting for 3 hours at room temperature, heating to 35 ℃, reacting for 15 hours again, and reacting fully; the specific steps of the step f are as follows: adding citric acid aqueous solution into the reaction system in the step e, adding glacial acetic acid, adjusting the pH to 2-3, and adding N 2 Under protection, the reaction temperature is raised to 40 ℃, and after 8 hours of reaction, the reaction is cooled to room temperature, so that the microcapsule with the capsule core material as the sterilizing disinfectant is obtained.
10. The microcapsules of claim 3, wherein the microcapsules of step (2) comprise the following components in parts by weight: 45-55 parts of gelatin, 3-7 parts of chitosan, 350 parts of 1.0% acetic acid solution 250-ion, 40-60 parts of soybean lecithin, 30-40 parts of 0.5% genipin aqueous solution, 5-15 parts of 1.0% citric acid aqueous solution and 3000 parts of vegetable oil 2500-ion.
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Citations (3)
| 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 |
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Patent Citations (3)
| 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)
| Title |
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| MIHAELA MOISE等: "Double crosslinked chitosan and gelatin submicronic capsules entrapping aminoacid derivatives with potential antitumoral activity", 《J MATER SCI.》, vol. 47, pages 8223 - 8233, XP035111375, DOI: 10.1007/s10853-012-6719-1 * |
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