CN112294843A - Long-acting wound antibacterial gel and preparation method thereof - Google Patents
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Abstract
The invention discloses a long-acting wound antibacterial gel which is prepared from the following raw materials in percentage by mass: 0.05-25% of silver-loaded slow-release hollow particles, 0.1-5% of chitosan antibacterial material, 0.01-2.5% of surfactant, 1-25% of humectant, 0.1-50% of gel matrix, 0.01-3% of complexing agent and the balance of deionized water, wherein the total amount of the components is 100%. The silver-loaded slow-release hollow particles added in the invention have high specific surface area, large pore volume and hollow cavities in the controllable pore diameter, so that a large amount of drug silver molecules are stored, and the drug silver conveying capacity is enhanced. Meanwhile, the silver-loaded slow-release hollow particles have controllable channels, so that the release speed of silver ions can be controlled, and the release time of the silver ions is prolonged. The chitosan antibacterial material is combined with the silver-loaded slow-release hollow particles, the silver-loaded slow-release hollow particles are connected to the chitosan dendritic molecular structure, the dissolution speed of the silver-loaded slow-release hollow particles is controlled, and the long-acting antibacterial function is realized. The invention provides a preparation method of long-acting wound antibacterial gel, which has the characteristics of easy operation and convenient batch production.
Description
Technical Field
The invention relates to a gel, in particular to a long-acting wound antibacterial gel and a preparation method thereof.
Background
Silver salts and silver complexes are now used to combat infection and control spoilage in a variety of pharmaceutical and health care applications, including anti-infective coatings in medical devices, post-operative wound treatment, and burn treatment. When a trace amount of silver ions reach the microbial cell membrane, the silver ions are firmly adsorbed by virtue of coulomb attraction because the silver ions carry negative charges, penetrate through the cell wall and enter the cell, so that protein is solidified, the activity of enzymes such as glucose, sucrose, urea and the like in the cell body is damaged, and the carboxyl (-COOH) and the sulfhydryl (-SH) of the cells are mainly damaged, so that the bacteria are killed. Silver has strong affinity to-SH enzyme contained in microorganisms, forms an irreversible sulfur-silver compound, binds-SH, interferes the respiration of the microorganisms, and causes cell death. Cell death can result from changes in cell osmolality and permeability caused by structural destruction of the bacteria. Silver is a parent metal, and a silver salt antibacterial agent is popular due to high antibacterial rate and lasting drug effect, but the silver salt is an oxidation type antibacterial agent and is easily harmful to a human body when being improperly used.
Most of traditional hydrogel materials are formed by directly compounding silver particles with an implant, so that the implant is endowed with an antibacterial function. After the nano silver ions are directly compounded with the hydrogel material, the nano silver particles have interaction with tissues or cells, but when the concentration of the nano silver particles exceeds a certain range, certain toxicity is generated on the cells and the tissues. Since the pores of the hydrogel are mostly in the micron or submicron level, the silver nanoparticles easily penetrate through the pores and rapidly escape to the outside of the stent material, so that the implant cannot achieve long-term antibacterial or bacteriostatic effects.
At present, most of the silver ion antibacterial agents in the market are in liquid forms with similar water viscosity, the retention time of the antibacterial agents in wounds or tissues is short, and the silver ion sterilization active ingredients are difficult to fully exert the sterilization effect. Meanwhile, collagen used in the existing antibacterial agent is negatively charged and can react with positively charged silver ions to generate precipitates, so that the product is ineffective and is not beneficial to killing bacteria.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the long-acting wound antibacterial gel which has the characteristics of quick and long-lasting sterilization effect, long-acting antibacterial property, low toxicity to cells and tissues and safe use.
The second purpose of the invention is to provide a preparation method of the long-acting wound antibacterial gel.
One of the purposes of the invention is realized by adopting the following technical scheme:
the long-acting wound antibacterial gel is prepared from the following raw materials in percentage by mass: 0.05-25% of silver-loaded slow-release hollow particles, 0.1-5% of chitosan antibacterial material, 0.01-2.5% of surfactant, 1-25% of humectant, 0.1-50% of gel matrix, 0.01-3% of complexing agent and the balance of deionized water, wherein the total amount of the components is 100%.
Further, the silver-loaded slow-release hollow particles take polyacrylic acid as a template agent,the silver-loaded slow-release hollow particle is prepared by taking hexamethyldisilane, dihydroxyaluminum aminoacetate, calcium hydroxyphosphate and a silver source as inorganic salt precursors, and the specific surface area of the silver-loaded slow-release hollow particle is 10-100m2G, pore volume of 0.1-1.6cm3The hollow cavity in the pore diameter is 10-100 nm.
Further, the molar ratio of the hexamethyldisilane, the aluminum dihydroxyglycinate, the calcium hydroxyphosphate and the silver source mixture is 75: 10: 15, wherein the molar ratio of the calcium hydroxyphosphate to the silver source is 10: 1-10.
Further, the silver source is at least one of silver nitrate, silver thiosulfate, silver sulfate and silver chloride.
Further, the chitosan antibacterial material is at least one of natural chitosan, chitosan quaternary ammonium salt or organic silicon quaternary ammonium salt.
Further, the surfactant is at least one of polycaprolactam, betaine, polyhexamethylene biguanide, quaternary ammonium salts and scale remover.
Further, the humectant is at least one of polyethylene glycol, glycerol, butanediol, propylene glycol, hexanediol and sodium hyaluronate.
Further, the gel matrix is at least one of carbomer 940, hydroxyethyl cellulose, sodium carboxymethyl cellulose, gelatin, xanthan gum, vaseline, ethyl cellulose and hydroxyethyl methyl cellulose.
Further, the complexing agent is at least one of monoethanolamine, diethanolamine and triethanolamine.
The second purpose of the invention is realized by adopting the following technical scheme:
the preparation method of the long-acting wound antibacterial gel comprises the following steps:
(1) preparing silver-loaded slow-release hollow particles: dissolving polyacrylic acid serving as a template agent in an ethanol solution, adding ammonia water, stirring, adding hexamethyldisilane, stirring for a period of time, adding dihydroxyaluminum aminoacetate, uniformly stirring, adding a mixture of calcium hydroxyphosphate and a silver source, uniformly stirring, centrifuging, drying and calcining to obtain silver-loaded slow-release hollow particles;
(2) mixing and grinding the silver-loaded slow-release hollow particles and the chitosan antibacterial material in the step (1), adding the mixture into deionized water, heating in a water bath, and stirring to obtain a chelate of the silver-loaded slow-release hollow particles and the chitosan antibacterial material;
(3) adding the gel matrix into deionized water for swelling to obtain a component A, dissolving a humectant in the deionized water to obtain a component B, adding the component B into the component A under the stirring state, adding a surfactant after uniformly mixing, adding the silver-loaded slow-release hollow particles obtained in the step (2) and the chitosan antibacterial material chelate, stirring for a period of time under the irradiation of infrared light, adding a complexing agent, fully stirring, adjusting the pH value to 6-8, standing and removing bubbles to obtain the product.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a long-acting wound antibacterial gel, and the added silver-loaded slow-release hollow particles have high specific surface area (10-100 m)2Per gram), large pore volume (0.1-1.6 cm)3The hollow cavity (10-100nm) in the controllable pore diameter enables the silver-containing composite material to store a large amount of drug silver molecules, and the drug silver conveying capacity is enhanced. After contacting the skin wound surface, the silver-loaded slow-release hollow particles can quickly release silver ions to kill pathogenic microorganisms, and meanwhile, the silver-loaded slow-release hollow particles are provided with controllable channels, namely hollow cavities in the pore diameters, so that the release speed of the silver ions can be controlled, the release time of the silver ions is prolonged, and the long-acting antibacterial function is realized. The silver-loaded slow-release hollow particles have good bioactivity and biocompatibility, can release silicon ions and calcium ions after contacting a wound surface, can activate gene expression related to wound healing, promote proliferation and differentiation of fibroblasts, accelerate angiogenesis, promote growth of granulation tissues, promote repair and regeneration of hard tissues and soft tissues, and promote wound healing.
The chitosan antibacterial material has good film forming property, forms a layer of macromolecular positive charge barrier while forming a physical barrier on the wound surface, and plays a role in sterilization and isolation as well as dual anti-infection. The chitosan antibacterial material is combined with the silver-loaded slow-release hollow particles, and the silver-loaded slow-release hollow particles are connected to the chitosan dendritic molecular structure, so that the gel has better film-forming property, the dissolution speed of the silver-loaded slow-release hollow particles is controlled, the long-acting antibacterial function is realized, and the bactericidal effect is more durable. The antibacterial gel has the functions of absorbing water and keeping moisture, forms a moist environment, and can quickly heal wounds in the moist environment, double the healing speed and reduce scar hyperplasia.
The surfactant can uniformly disperse the silver-loaded slow-release hollow particles in the gel to form a stable structure, and meanwhile, the surfactant and silver ions are cooperated for antibiosis, so that the sterilization performance of the gel is enhanced, and the toxicity to cells and tissues is lower.
Drawings
FIG. 1 is a scanning electron microscope image of silver-loaded sustained-release particles in example 1 of the present invention;
FIG. 2 is a scanning electron microscope image of chelates of silver-loaded sustained-release hollow particles and chitosan antibacterial materials in example 1 of the present invention;
fig. 3 is a release curve of silver ions in deionized water of the silver-loaded slow-release particles and the antibacterial gel in example 1 of the present invention.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
Example 1
The long-acting wound antibacterial gel is prepared from the following raw materials in percentage by mass: 5% of silver-loaded slow-release hollow particles, 3% of natural chitosan, 1% of polyhexamethylene guanidine, 10% of polyethylene glycol, 94025% of carbomer, 2% of monoethanolamine and the balance of deionized water, wherein the total amount of the components is 100%.
The silver-loaded slow-release particles comprise the following components: the molar ratio of hexamethyldisilane, aluminum dihydroxyaminoacetate, calcium hydroxyphosphate and silver source mixture is 75: 10: 15, wherein the molar ratio of calcium hydroxyphosphate and silver source is 10: 1.
The preparation method of the long-acting wound antibacterial gel comprises the following steps:
(1) preparing silver-loaded slow-release hollow particles: dissolving 1.0g of polyacrylic acid in 300mL of ethanol solution, stirring until the solution is clear, adding 20mL of ammonia water, magnetically stirring for 1h, adding 0.2mol of hexamethyldisilane, stirring for 8h, adding 0.0267mol of dihydroxyaluminum aminoacetate, stirring for 2h, adding 0.04mol of a mixture of calcium hydroxy phosphate and a silver source, stirring for 6h, centrifugally cleaning for three times, carrying out infrared heating and drying for 10h, placing the obtained powder in a muffle furnace with the heating rate of 3 ℃/min and the temperature of 850 ℃ for calcining for 4h, and obtaining the silver-loaded slow-release hollow particles, wherein the formula is shown in figure 1;
(2) mixing the silver-loaded slow-release hollow particles obtained in the step (1) with a chitosan antibacterial material, fully and quickly grinding for 3 hours, adding the mixture into deionized water, heating in a water bath, and stirring to obtain a chelate of the silver-loaded slow-release hollow particles and the chitosan antibacterial material;
(3) adding the gel matrix into deionized water for swelling to obtain a component A, dissolving a humectant in the deionized water to obtain a component B, adding the component B into the component A under the stirring state, adding a surfactant after uniformly mixing, adding the silver-loaded slow-release hollow particles obtained in the step (2) and the chitosan antibacterial material chelate, stirring for a period of time under the irradiation of infrared light, adding a complexing agent, fully stirring, adjusting the pH value to 6-8, standing and removing bubbles to obtain the product, wherein the product is shown in figure 2.
Example 2
The long-acting wound antibacterial gel is prepared from the following raw materials in percentage by mass: 10% of silver-loaded slow-release hollow particles, 4% of chitosan quaternary ammonium salt, 2% of betaine, 5% of glycerol, 30% of hydroxyethyl cellulose, 3% of diethanolamine, and the balance of deionized water, wherein the total amount of the components is 100%.
The silver-loaded slow-release particles comprise the following components: the molar ratio of hexamethyldisilane, aluminum dihydroxyaminoacetate, calcium hydroxyphosphate and silver source mixture is 75: 10: 15, wherein the molar ratio of calcium hydroxyphosphate and silver source is 10: 3.
The preparation method of this example is the same as example 1.
Example 3
The long-acting wound antibacterial gel is prepared from the following raw materials in percentage by mass: 0.05% of silver-loaded slow-release hollow particles, 0.1% of a mixture of natural chitosan and organosilicon quaternary ammonium salt, 0.01% of a mixture of betaine and polyhexamethylene biguanide, 1% of butanediol and propylene glycol, 1% of sodium carboxymethylcellulose and gelatin, 0.01% of a mixture of diethanolamine and triethanolamine, and the balance of deionized water, wherein the total amount of the components is 100%.
The silver-loaded slow-release particles comprise the following components: the molar ratio of hexamethyldisilane, aluminum dihydroxyaminoacetate, calcium hydroxyphosphate and silver source mixture is 75: 10: 15, wherein the molar ratio of calcium hydroxyphosphate and silver source is 10: 5.
The preparation method of the example is the same as that of the example 1.
Example 4
The long-acting wound antibacterial gel is prepared from the following raw materials in percentage by mass: 25% of silver-loaded slow-release hollow particles, 5% of natural chitosan, 2.5% of scale, 25% of sodium hyaluronate, 40% of hydroxyethyl methyl cellulose, 3% of triethanolamine and the balance of deionized water, wherein the total amount of the components is 100%.
The silver-loaded slow-release particles comprise the following components: the molar ratio of hexamethyldisilane, aluminum dihydroxyaminoacetate, calcium hydroxyphosphate and silver source mixture is 75: 10: 15, wherein the molar ratio of calcium hydroxyphosphate and silver source is 10: 10.
The preparation method of the example is the same as that of the example 1.
Comparative example 1
Comparative example 1 provides an antibacterial gel, which is different from example 1 in that: the silver-carrying slow-release hollow particles are replaced by silver nitrate with the same silver content.
Comparative example 2
Comparative example 2 provides an antibacterial gel, which is different from example 1 in that: the silver source is saved in the preparation process of the silver-loaded slow-release hollow particles, the prepared product is soaked in silver nitrate solution for 12 hours and then chelated with the chitosan antibacterial material, and the rest is the same as that in the embodiment 1.
Test examples
Bacteriostatic ring experiment: examples 1 and comparative examples 1 to 2 were tested for bacteriostatic effects against staphylococcus aureus (ATCC 6538), candida albicans (ATCC 10231), respectively, as follows: activating and diluting the strain to 2 × 106cfu/ml, test suspension dipped with sterile cottonThe solution is evenly smeared on the surface of a nutrient agar culture medium plate for 3 times. The products of example 1 and comparative examples 1 to 2 were diluted to a concentration of 200mg/l using hot nutrient agar, 20. mu.l of the diluted solution was pipetted onto the nutrient agar medium, and the medium was incubated at 37 ℃ for 24 hours in an incubator and the results were observed. The size of the zone was measured with a vernier caliper and compared. 3 dishes of each inoculum were prepared in parallel, and the results are shown in Table 1 below.
TABLE 1
It can be seen from table 1 that on the first day, the diameter of the bacteriostatic ring of example 1 is smaller than that of comparative example 1 and comparative example 2, and the diameter of the bacteriostatic ring of example 1 begins to exceed that of comparative example 1 and comparative example 2 with the increase of time, which shows that the silver-loaded sustained-release hollow particles provided by the invention can control the release rate of silver ions, prolong the release time of silver ions, make the bactericidal efficacy of the silver-loaded sustained-release hollow particles more durable, and realize the long-acting antibacterial function.
The silver-loaded sustained-release hollow particles prepared in example 1 and the antibacterial gel prepared in example 1 with the same silver content were leached in deionized water, the content of silver ions in the deionized water was detected, and the release curve of the silver ions in the deionized water was plotted, and the results are shown in fig. 3. As can be seen from FIG. 3, the accumulation amount of silver in the aqueous solution of the silver-loaded slow-release hollow particles is higher than that of the antibacterial gel along with the prolonging of time, which shows that the silver release speed of the silver-loaded slow-release hollow particles is higher than that of the antibacterial gel.
The antimicrobial gel of example 1 was made into a suspension to test its killing effect on microorganisms as follows: the carrier for the bacteria is made of degreased cotton cloth. The sterile plate was removed and 15ml of the antimicrobial gel solution was pipetted into the plate. 3 pieces of the bacterial carrier bacterial sheet were put into the sterile forceps, and soaked in the antibacterial gel solution. Taking out the bacterial tablets by using sterile forceps after the bacterial drugs interact for 1, 2 and 5min, and respectively transferring the bacterial tablets into test tubes containing 5.0ml of neutralizing agent. Mixing for 20s with electric mixer to elute bacteria on the bacterial sheet into the neutralizing solution, neutralizing for 5min, mixing, sucking 1.0ml, inoculating into plate, inoculating 2 plates per tube, and determining viable bacteria number. All test samples were incubated in an incubator at 37 ℃ and the results are shown in Table 2.
TABLE 2
As can be seen from Table 2, the sterilization index of the antibacterial gel to staphylococcus aureus, pseudomonas aeruginosa and escherichia coli is greater than 6.00 at 1min, the sterilization index of candida albicans is greater than 5.00, and the sterilization index is greater than 6.0 at 5min, which shows that the antibacterial gel has good sterilization effect.
Primary damaged skin irritation test: 4 healthy rabbits were used as the experimental subjects, and a "well" -shaped damaged wound was made in the skin area with a sterile blade, the skin was damaged only to the epidermis without damaging the dermis, and the damaged skin area was contaminated with the toxin. The antibacterial gel of example 1 was then applied to the damaged skin and the skin reaction was observed, with the results shown in table 3 and table 4 as skin irritation response scoring criteria.
TABLE 3
| Rabbit number | Skin(s)Stimulus response scoring |
| 1 | 0 |
| 2 | 0.15 |
| 3 | 0.12 |
| 4 | 0 |
Note: (1) erythema formation: no 0 point, barely 1 point, obvious 2 points and serious 3 points; purplish red erythema with eschar 4 points;
(2) edema formation, no 0 point, barely visible 1 point, skin bulge, clear outline 2 points, edema bulge of about 1mm 3 points; edema swelling over 1mm 4 points;
average per animal per day ═ Σ (total integration of erythema and edema of 14d per animal)/number of test animals × 14
TABLE 4 skin irritation response Scoring criteria
| Index of skin irritation | |
| 0～＜0.5 | Has no irritation |
| 0.5～＜2.0 | Light irritation |
| 2.0～＜6.0 | Moderate irritation |
| 6.0～8.0 | Strong irritation |
As can be seen from Table 3: the skin irritation response scores of 4 rabbits are all less than 0.5, and the results show that the antibacterial gel has no irritation.
Eye irritation test: using 3 healthy rabbits as the subjects, 0.1ml of the antibacterial gel of example 1 was aspirated and dropped into the conjunctival sac of one side of the rabbit. The other eye was treated with normal saline as a normal control. After instillation of the test article, the eye was passively closed for 4s, and then rinsed with saline 30s later. The rabbit eyes were visually observed for damage and recovery of conjunctiva, iris and cornea 1h, 24h, 48h, 72h, 7d, 14d and 21d after eye dropping, and the results are shown in table 5.
TABLE 5
As can be seen from Table 5, the gel of the present application showed no irritation to three rabbits, further indicating that the antibacterial gel of the present application has low toxicity to cells and tissues and is safe to use.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. The long-acting wound antibacterial gel is characterized by being prepared from the following raw materials in percentage by mass: 0.05-25% of silver-loaded slow-release hollow particles, 0.1-5% of chitosan antibacterial material, 0.01-2.5% of surfactant, 1-25% of humectant, 0.1-50% of gel matrix, 0.01-3% of complexing agent and the balance of deionized water, wherein the total amount of the components is 100%.
2. The long-acting wound antibacterial gel according to claim 1, wherein the silver-loaded slow-release hollow particles are prepared by taking polyacrylic acid as a template agent and hexamethyldisilane, dihydroxyaluminum aminoacetate, calcium hydroxyphosphate and a silver source as inorganic salt precursors, and the specific surface area of the silver-loaded slow-release hollow particles is 10-100m2G, pore volume of 0.1-1.6cm3The hollow cavity in the pore diameter is 10-100 nm.
3. The long-acting wound antiseptic gel of claim 2 wherein the molar ratio of the mixture of hexamethyldisilane, aluminum dihydroxyglycinate, calcium hydroxyphosphate and silver source is 75: 10: 15, wherein the molar ratio of the calcium hydroxyphosphate to the silver source is 10: 1-10.
4. The long-acting wound antiseptic gel of claim 1 wherein the silver source is at least one of silver nitrate, silver thiosulfate, silver sulfate, silver chloride.
5. The long-acting wound antibacterial gel according to claim 1, wherein the chitosan antibacterial material is at least one of natural chitosan, chitosan quaternary ammonium salt or organosilicon quaternary ammonium salt.
6. The long-acting wound antiseptic gel of claim 1 wherein the surfactant is at least one of polycaprolactam, betaine, polyhexamethylene biguanide, quaternary ammonium salts, descale.
7. The long-acting wound antibacterial gel according to claim 1, wherein the humectant is at least one of polyethylene glycol, glycerol, butylene glycol, propylene glycol, hexylene glycol and sodium hyaluronate.
8. The long-acting wound antiseptic gel of claim 1 wherein the gel matrix is at least one of carbomer 940, hydroxyethyl cellulose, sodium carboxymethyl cellulose, gelatin, xanthan gum, petrolatum, ethyl cellulose, hydroxyethyl methyl cellulose.
9. The long-acting wound antibacterial gel according to claim 1, wherein the complexing agent is at least one of monoethanolamine, diethanolamine and triethanolamine.
10. A method of preparing a long-acting wound-surface antimicrobial gel as claimed in claim 2, comprising the steps of:
(1) preparing silver-loaded slow-release hollow particles: dissolving polyacrylic acid serving as a template agent in an ethanol solution, adding ammonia water, stirring, adding hexamethyldisilane, stirring for a period of time, adding dihydroxyaluminum aminoacetate, uniformly stirring, adding a mixture of calcium hydroxyphosphate and a silver source, uniformly stirring, centrifuging, drying and calcining to obtain silver-loaded slow-release hollow particles;
(2) mixing and grinding the silver-loaded slow-release hollow particles and the chitosan antibacterial material in the step (1), adding the mixture into deionized water, heating in a water bath, and stirring to obtain a chelate of the silver-loaded slow-release hollow particles and the chitosan antibacterial material;
(3) adding the gel matrix into deionized water for swelling to obtain a component A, dissolving a humectant in the deionized water to obtain a component B, adding the component B into the component A under the stirring state, adding a surfactant after uniformly mixing, adding the silver-loaded slow-release hollow particles obtained in the step (2) and the chitosan antibacterial material chelate, stirring for a period of time under the irradiation of infrared light, adding a complexing agent, fully stirring, adjusting the pH value to 6-8, standing and removing bubbles to obtain the product.
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Citations (5)
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